WO2025256641A1 - 抗pd-l1抗体和抗ctla-4抗体联合治疗肿瘤 - Google Patents

抗pd-l1抗体和抗ctla-4抗体联合治疗肿瘤

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Publication number
WO2025256641A1
WO2025256641A1 PCT/CN2025/100955 CN2025100955W WO2025256641A1 WO 2025256641 A1 WO2025256641 A1 WO 2025256641A1 CN 2025100955 W CN2025100955 W CN 2025100955W WO 2025256641 A1 WO2025256641 A1 WO 2025256641A1
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WO
WIPO (PCT)
Prior art keywords
antibody
once
weeks
approximately
ctla
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/100955
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English (en)
French (fr)
Inventor
王姝妮
张允�
耿皓
王焕
孙颖
唐芊
李伟霞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hengrui Pharmaceutical Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
Original Assignee
Jiangsu Hengrui Pharmaceutical Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Hengrui Pharmaceutical Co Ltd, Shanghai Shengdi Pharmaceutical Co Ltd filed Critical Jiangsu Hengrui Pharmaceutical Co Ltd
Publication of WO2025256641A1 publication Critical patent/WO2025256641A1/zh
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • This disclosure pertains to the pharmaceutical field and relates to methods and pharmaceutical uses for the combined treatment of tumors with anti-PD-L1 antibodies and anti-CTLA-4 antibodies.
  • the human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene is located on the long arm of chromosome 2, region 3, band 3 (2q33), and is mainly expressed on the surface of activated T lymphocytes. It shares a very close relationship with the costimulatory molecule receptor (CD28) on the T cell surface in terms of gene structure, chromosomal location, sequence homology, and gene expression. It can bind to the costimulatory molecule (B7) on the surface of antigen-presenting cells (APCs). However, unlike CD28, CTLA-4 inhibits T cell activation after binding to B7.
  • CD28 costimulatory molecule receptor
  • APCs antigen-presenting cells
  • CTLA-4 As CTLA-4 expression increases on activated T cells, it competitively binds to B7 molecules alongside CD28 in the later stages of the immune response, inhibiting T cell transition from the G phase to the S phase and suppressing the activity of IL-2 transcription factor, thereby downregulating or terminating the T cell response. Therefore, CTLA-4 is considered an immune factor that inhibits the body's anti-tumor activity. Developing safer and more effective immunotherapy regimens against tumors using anti-CTLA-4 antibodies is a crucial issue that needs to be addressed in the field of targeted immunotherapy for tumors.
  • This disclosure provides a method for treating tumors with anti-PD-L1 antibody drugs in combination with anti-CTLA-4 antibodies and their pharmaceutical applications.
  • this disclosure provides for any of the following uses:
  • the anti-PD-L1 antibody is used to treat tumors, wherein the anti-PD-L1 antibody is administered in combination with the anti-CTLA-4 antibody to the subject;
  • the anti-CTLA-4 antibody is used to treat tumors, wherein the anti-CTLA-4 antibody is administered in combination with the anti-PD-L1 antibody to the subject;
  • Anti-PD-L1 antibody is used to treat subjects with tumors, wherein the subjects are also given anti-CTLA-4 antibody;
  • Anti-CTLA-4 antibody is used to treat subjects with tumors, wherein the subjects are also given anti-PD-L1 antibody.
  • this disclosure provides a method of treating tumors, including administering therapeutically effective amounts of anti-PD-L1 antibodies and anti-CTLA-4 antibodies to a subject in need.
  • any of the foregoing methods or uses may be further combined with chemotherapeutic agents, antibodies with antitumor activity, antibody-drug conjugates, and/or antiangiogenic agents.
  • this disclosure provides for any of the following uses:
  • anti-PD-L1 antibody in combination with anti-CTLA-4 antibody and anti-angiogenic agent in the preparation of drugs for treating tumors;
  • the anti-PD-L1 antibody is used to treat tumors, wherein the anti-PD-L1 antibody is administered to the subject in combination with an anti-CTLA-4 antibody and an anti-angiogenic agent;
  • the anti-CTLA-4 antibody is used to treat tumors, wherein the anti-CTLA-4 antibody is administered to the subject in combination with an anti-PD-L1 antibody and an anti-angiogenic agent;
  • Anti-PD-L1 antibody is used to treat subjects with tumors, wherein the subjects are also given anti-CTLA-4 antibody and anti-angiogenic agent;
  • Anti-CTLA-4 antibody is used to treat subjects with tumors, wherein the subjects are also given anti-PD-L1 antibody and anti-angiogenic agent.
  • this disclosure provides a method of treating tumors, including administering a therapeutically effective amount of an anti-PD-L1 antibody, an anti-CTLA-4 antibody, and an anti-angiogenic agent to a subject in need.
  • this disclosure provides for any of the following uses:
  • the anti-PD-L1 antibody is used to treat tumors, wherein the anti-PD-L1 antibody is administered to the subject in combination with the anti-CTLA-4 antibody and a chemotherapeutic agent;
  • the anti-CTLA-4 antibody is used to treat tumors, wherein the anti-CTLA-4 antibody is administered to the subject in combination with an anti-PD-L1 antibody and a chemotherapeutic agent;
  • Anti-PD-L1 antibody is used to treat subjects with tumors, wherein the subjects are also given anti-CTLA-4 antibody and chemotherapy agents;
  • Anti-CTLA-4 antibody is used to treat subjects with tumors, wherein the subjects are also given anti-PD-L1 antibody and chemotherapy agents.
  • this disclosure provides a method of treating tumors, including administering a therapeutically effective amount of an anti-PD-L1 antibody, an anti-CTLA-4 antibody, and a chemotherapeutic agent to a subject in need.
  • the anti-CTLA-4 antibody is used in combination with anti-PD-L1 and not in combination with an anti-Nectin-4 antibody-drug conjugate.
  • the anti-Nectin-4 antibody-drug conjugate is derived from any structure of antibody-drug conjugates in WO2022228406A and WO2023221971A.
  • the tumor is a solid tumor. In some embodiments, the tumor is a malignant solid tumor.
  • malignant solid tumor refers to a tumor that is carcinogenic.
  • Carcinogenic tumors can invade surrounding tissues within the body, and as these tumors grow, some cancer cells may migrate to other parts of the body to form other "secondary" tumors, also known as metastases.
  • the tumor is an advanced, recurrent, or metastatic solid tumor. In some embodiments, the tumor is a solid tumor that has failed standard treatment. In some embodiments, the tumor is a solid tumor that has not received standard treatment. In some embodiments, the patient with the tumor receives systemic antitumor therapy. In some embodiments, the patient with the tumor does not receive systemic antitumor therapy.
  • systemic anti-tumor treatment regimens are well known to those skilled in the art, such as those disclosed in regulatory-approved treatment guidelines. Examples include, but are not limited to, detailed and up-to-date information on standard treatment regimens for various cancers provided in NCCN and CSCO guidelines.
  • the tumor is selected from liver cancer, lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), and biliary tract cancer.
  • the tumor is liver cancer.
  • the liver cancer is unresectable locally advanced or metastatic liver cancer.
  • the liver cancer is stage B or C in the BCLC (Barcelona Clinical Hepatocellular Carcinoma Staging) system.
  • the tumor is non-small cell lung cancer. In some specific implementations, it is histologically or cytologically confirmed recurrent or advanced NSCLC. In some specific implementations, it is non-small cell lung cancer with PD-L1 TPS ⁇ 50%.
  • the tumor is selected from squamous or non-squamous NSCLC.
  • the subjects are those with histologically or cytologically confirmed advanced or metastatic non-squamous NSCLC.
  • Advanced stage is defined as stage IIIB according to the International Association for the Study of Lung Cancer (TNM staging system, 8th edition), and who are no longer suitable for radical surgery or radiotherapy.
  • the driver gene-positive non-small cell lung cancer is defined as STK11, KEAP1, or KRAS-mutated or co-mutated non-small cell lung cancer.
  • the tumor is biliary adenocarcinoma; in some embodiments, the tumor is gallbladder cancer, intrahepatic bile duct cancer, or extrahepatic bile duct cancer; in some embodiments, the tumor is locally advanced or recurrent/metastatic gallbladder cancer, intrahepatic bile duct cancer, or extrahepatic bile duct cancer.
  • the tumor is a histologically or cytologically confirmed, unresectable locally advanced, or recurrent/metastatic gallbladder cancer, intrahepatic cholangiocarcinoma, or extrahepatic cholangiocarcinoma.
  • the anti-PD-L1 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:1-3, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:4-6.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-PD-L1 antibody comprises any one of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, or any combination of two, three, four, five, or six of them.
  • the anti-PD-L1 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL): wherein the VH comprises HCDR1, HCDR2, and HCDR3 of the amino acid sequence shown in SEQ ID NO:7, and the VL comprises LCDR1, LCDR2, and LCDR3 of the amino acid sequence shown in SEQ ID NO:8.
  • VH heavy chain variable region
  • VL light chain variable region
  • the aforementioned CDRs are defined according to the Kabat, IMGT, Chothia, AbM, or Contact definition schemes. In some specific embodiments, the CDRs are defined according to the Kabat definition scheme.
  • the anti-PD-L1 antibody is a chimeric, humanized, fully human antibody or its antigen-binding fragment.
  • the anti-PD-L1 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an amino acid sequence as shown in or having at least 80% or 90% identity with SEQ ID NO:7, and the VL comprises an amino acid sequence as shown in or having at least 80% or 90% identity with SEQ ID NO:8.
  • VH heavy chain variable region
  • VL light chain variable region
  • the underlined part is the CDR area determined according to the Kabat numbering rules.
  • the anti-PD-L1 antibody comprises any one or both of the aforementioned VH and VL.
  • the anti-PD-L1 antibody further comprises a heavy chain constant region and/or a light chain constant region.
  • the heavy chain constant region of the antibody may be selected from the constant regions of human IgG1, IgG2, IgG3, IgG4, and their variants.
  • the light chain constant region may be selected from the light chain constant region of human ⁇ , ⁇ chains, or their variants.
  • the anti-PD-L1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO:9 or having at least 80% or at least 90% sequence identity with it; and/or, the light chain comprises an amino acid sequence as shown in SEQ ID NO:10 or having at least 80% or at least 90% sequence identity with it.
  • the anti-PD-L1 antibody comprises a heavy chain with an amino acid sequence as shown in SEQ ID NO:9 and a light chain with an amino acid sequence as shown in SEQ ID NO:10.
  • the underlined portion is the variable region sequence of the antibody heavy or light chain
  • the ununderlined portion is the constant region sequence of the antibody.
  • the preparation of the above-mentioned anti-PD-L1 antibody or its antigen-binding fragment can refer to WO2017084495A1 and WO2018210230A1.
  • the relevant contents of antibody sequences, preparation methods and compositions in WO2017084495A1 and WO2018210230A1 are incorporated herein by reference.
  • At least 80% or 90% encompasses 80% and above, such as at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and any numerical range between the two.
  • the dosage of the anti-PD-L1 antibody is 50 mg to 5000 mg, for example 100 mg to 5000 mg, 100 mg to 4500 mg, 100 mg to 4000 mg, 100 mg to 3500 mg, 100 mg to 3000 mg, 100 mg to 2500 mg, 100 mg to 2000 mg, 100 mg to 1500 mg, 500 mg to 3500 mg, 500 mg to 3000 mg.
  • the dosage of the anti-PD-L1 antibody is approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, 225 mg, approximately 250 mg, approximately 375 mg, approximately 400 mg, approximately 425 mg, approximately 450 mg, approximately 475 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, 650 mg, approximately 700 mg, approximately 750 mg, approximately 80 mg, etc.
  • the dosage of the anti-PD-L1 antibody is approximately 1200 mg or approximately 1800 mg.
  • the dosage of the anti-PD-L1 antibody is 1 mg/kg-500 mg/kg, 1 mg/kg-50 mg/kg, 5 mg/kg-50 mg/kg, 10 mg/kg-50 mg/kg, 15 mg/kg-50 mg/kg, 20 mg/kg-50 mg/kg, 1 mg/kg-30 mg/kg, 5 mg/kg-30 mg/kg, 10 mg/kg-30 mg/kg, or 15 mg/kg-30 mg/kg; or any range between these values.
  • the dosage of the anti-PD-L1 antibody is about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 ...
  • mg/kg approximately 29 mg/kg, approximately 30 mg/kg, approximately 35 mg/kg, approximately 40 mg/kg, approximately 45 mg/kg, approximately 50 mg/kg, approximately 55 mg/kg, approximately 60 mg/kg, approximately 65 mg/kg, approximately 70 mg/kg, approximately 75 mg/kg, approximately 80 mg/kg, approximately 85 mg/kg, approximately 90 mg/kg, approximately 95 mg/kg, approximately 110 mg/kg, approximately 120 mg/kg, approximately 130 mg/kg, approximately 140 mg/kg, approximately 150 mg/kg, approximately 200 mg/kg, approximately 220 mg/kg, approximately 250 mg/kg, approximately 300 mg/kg. Or any range of values between these points.
  • the dosage of the anti-PD-L1 antibody is about 20 mg/kg.
  • the anti-PD-L1 antibody is administered once every 2 weeks, once every 3 weeks, once every 4 weeks, or once every 6 weeks. In some specific embodiments, the anti-PD-L1 antibody is administered once every 3 weeks or once every 4 weeks.
  • the anti-PD-L1 antibody is administered via intravenous injection.
  • the anti-CTLA-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:11-13, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:14-16.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-CTLA-4 antibody comprises any one of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, or any combination of two, three, four, five, or six of them.
  • the anti-CTLA-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL): wherein the VH comprises HCDR1, HCDR2, and HCDR3 of the amino acid sequence shown in SEQ ID NO:17, and the VL comprises LCDR1, LCDR2, and LCDR3 of the amino acid sequence shown in SEQ ID NO:18.
  • VH heavy chain variable region
  • VL light chain variable region
  • the aforementioned CDRs are defined according to the Kabat, IMGT, Chothia, AbM, or Contact definition schemes. In some specific embodiments, the CDRs are defined according to the Kabat definition scheme.
  • the anti-CTLA-4 antibody is a chimeric, humanized, fully human antibody or its antigen-binding fragment.
  • the anti-CTLA-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an amino acid sequence as shown in or having at least 80% or 90% identity with SEQ ID NO:17, and the VL comprises an amino acid sequence as shown in or having at least 80% or 90% identity with SEQ ID NO:18.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-CTLA-4 antibody comprises any one or both of the aforementioned VH and VL.
  • the anti-CTLA-4 antibody further comprises a heavy chain constant region and/or a light chain constant region.
  • the heavy chain constant region of the antibody may be selected from the constant regions of human IgG1, IgG2, IgG3, IgG4, and their variants.
  • the light chain constant region may be selected from the light chain constant region of human ⁇ , ⁇ chains, or their variants.
  • the anti-CTLA-4 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO:19 or having at least 80% or at least 90% sequence identity with it; and/or, the light chain comprises an amino acid sequence as shown in SEQ ID NO:20 or having at least 80% or at least 90% sequence identity with it.
  • the anti-CTLA-4 antibody comprises a heavy chain with an amino acid sequence as shown in SEQ ID NO:19 and a light chain with an amino acid sequence as shown in SEQ ID NO:20.
  • the underlined portion is the variable region sequence of the antibody heavy or light chain
  • the ununderlined portion is the constant region sequence of the antibody.
  • the dosage of the anti-CTLA-4 antibody is 0.1-50 mg/kg, for example 0.5-50 mg/kg, 0.1-20 mg/kg, 0.5-10 mg/kg, 0.5-8 mg/kg, 0.5-6 mg/kg, 0.5-5 mg/kg, 1-50 mg/kg, 1-20 mg/kg, 1-10 mg/kg, 1-3.5 mg/kg, 1-4 mg/kg, 0.5-3.5 mg/kg, 3.5-10 mg/kg, 3.5-8 mg/kg, 3.5-6 mg/kg, 4-6 mg/kg; or any range between these values.
  • the dosage of the anti-CTLA-4 antibody is about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 2.0 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, about 3.5 mg/kg, about 4.0 mg/kg, about 5.0 mg/kg, about 6.0 mg/kg, and about 7.0 mg/kg.
  • the dose of the anti-CTLA-4 antibody is approximately 1.0 mg/kg or approximately 4.0 mg/kg.
  • the dosage of the anti-CTLA-4 antibody is 5-1000 mg, for example 5-800 mg, 5-600 mg, 5-550 mg, 5-500 mg, 5-450 mg, 5-400 mg, 5-350 mg, 5-300 mg, 10-200 mg, 10-300 mg, 10-350 mg, 10-400 mg, 10-500 mg, 10-600 mg, 10-800 mg, 30-200 mg, 30-220 mg, 30-250 mg, 30-280 mg, 30-300 mg, 30-400 mg, 3 0-500mg, 30-600mg, 30-800mg, 50-800mg, 50-600mg, 50-550mg, 50-500mg, 50-450mg, 50-400mg, 50-350mg, 50-300mg, 100-800mg, 100-600mg, 100-550mg, 100-1000mg, 100-450mg, 100-400mg, 100-350mg, 100-300mg, 150-300mg, 150-400mg, 200-300mg, 200-400mg. Or any numerical range between these point values.
  • the dosage of the anti-CTLA-4 antibody is about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, or about 230 mg.
  • the dose of the anti-CTLA-4 antibody is approximately 70 mg or approximately 280 mg.
  • the anti-CTLA-4 antibody is administered once or multiple times. In some embodiments, the anti-CTLA-4 antibody is administered once or twice. In some embodiments, the anti-CTLA-4 antibody is administered once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, once every 12 weeks, once every 14 weeks, or once every 16 weeks.
  • the dosing regimen of the anti-CTLA-4 antibody is as follows:
  • the dosage is 3.5-10 mg/kg, administered once or twice; or,
  • the dosage is 220-360 mg, administered once or twice; or,
  • the dosage is 0.5-3.5 mg/kg, administered once every 3 weeks, once every 6 weeks, or once every 9 weeks; or,
  • the dosage is 30-220 mg, administered once every 3 weeks, once every 6 weeks or once every 9 weeks.
  • the dosing regimen of the anti-CTLA-4 antibody is as follows:
  • the dosage is about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg or about 6 mg/kg, administered once or twice;
  • the dosage is about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, or about 360 mg, administered once or twice;
  • the dosage is approximately 1.0 mg/kg, approximately 1.5 mg/kg, approximately 2 mg/kg, approximately 2.5 mg/kg, approximately 3.0 mg/kg or approximately 3.5 mg/kg; administered once every 3 weeks, once every 6 weeks or once every 9 weeks;
  • the dosage is about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 150 mg, about 170 mg, about 190 mg, or about 200 mg; once every 3 weeks, once every 6 weeks, or once every 9 weeks.
  • the dosing regimen of the anti-CTLA-4 antibody includes dosing phase I and dosing phase II; wherein:
  • the anti-CTLA-4 antibody is administered once or twice at a dose of 3.5-10 mg/kg/time;
  • the anti-CTLA-4 antibody is administered once every 6 weeks at a dose of 0.5-3.5 mg/kg.
  • the dosing regimen of the anti-CTLA-4 antibody includes dosing phase I and dosing phase II; wherein:
  • the anti-CTLA-4 antibody is administered once or twice at a dose of about 3.5 mg/kg/time, about 4 mg/kg/time, about 4.5 mg/kg/time, about 5 mg/kg/time, about 5.5 mg/kg/time, about 6 mg/kg/time or about 8 mg/kg/time;
  • the anti-CTLA-4 antibody is administered once every 6 weeks at a dose of about 0.5 mg/kg, about 1.0 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg or about 3.5 mg/kg.
  • the dosing regimen of the anti-CTLA-4 antibody includes dosing phase I and dosing phase II; wherein:
  • the anti-CTLA-4 antibody is administered once or twice at a dose of 3.5-10 mg/kg/time;
  • the anti-CTLA-4 antibody was administered once every 6 weeks at a dose of 30-150 mg.
  • the dosing regimen of the anti-CTLA-4 antibody includes dosing phase I and dosing phase II; wherein:
  • the anti-CTLA-4 antibody is administered once or twice at a dose of about 3.5 mg/kg/time, about 4 mg/kg/time, about 4.5 mg/kg/time, about 5 mg/kg/time, about 5.5 mg/kg/time, about 6 mg/kg/time or about 8 mg/kg/time;
  • the anti-CTLA-4 antibody is administered once every 6 weeks at a dose of about 30 mg, about 50 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, or about 150 mg.
  • the dosing regimen of the anti-CTLA-4 antibody includes dosing phase I and dosing phase II; wherein:
  • the anti-CTLA-4 antibody is administered once or twice at a dose of 220-360 mg/time;
  • the anti-CTLA-4 antibody was administered once every 6 weeks at a dose of 30-150 mg.
  • the dosing regimen of the anti-CTLA-4 antibody includes dosing phase I and dosing phase II; wherein:
  • the anti-CTLA-4 antibody is administered once or twice at a dose of about 220 mg/time, about 240 mg/time, about 260 mg/time, about 270 mg/time, about 280 mg/time, about 290 mg/time, about 300 mg/time, about 320 mg/time, about 340 mg/time, or about 360 mg/time;
  • the anti-CTLA-4 antibody is administered once every 6 weeks at a dose of about 30 mg, about 50 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, or about 150 mg.
  • the dosing regimen of the anti-CTLA-4 antibody includes dosing phase I and dosing phase II; wherein:
  • the anti-CTLA-4 antibody is administered once or twice at a dose of 220-360 mg/time;
  • the anti-CTLA-4 antibody is administered once every 6 weeks at a dose of 0.5-3.5 mg/kg.
  • the dosing regimen of the anti-CTLA-4 antibody includes dosing phase I and dosing phase II; wherein:
  • the anti-CTLA-4 antibody is administered once or twice at a dose of about 220 mg/time, about 240 mg/time, about 260 mg/time, about 270 mg/time, about 280 mg/time, about 290 mg/time, about 300 mg/time, about 320 mg/time, about 340 mg/time, or about 360 mg/time;
  • the anti-CTLA-4 antibody is administered once every 6 weeks at a dose of about 0.5 mg/kg, about 1.0 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg or about 3.5 mg/kg.
  • the dosing period I is at least 8 weeks, at least 10 weeks, or at least 12 weeks. In some embodiments, the dosing period I is 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 20 weeks, 24 weeks, or 30 weeks, etc.
  • the timing of dosing period I and dosing period II can be determined by clinical treatment efficacy.
  • the dosing regimen of the anti-CTLA-4 antibody is selected from:
  • the dosage is approximately 4.0 mg/kg or approximately 280 mg, administered once or twice;
  • the dosage is approximately 1.0 mg/kg, administered once every 3 weeks, once every 6 weeks, or once every 9 weeks;
  • dosing period I administer a single dose of approximately 4.0 mg/kg; then, during dosing period II, administer a dose of approximately 1.0 mg/kg every 6 weeks.
  • dosing period I administer a single dose of approximately 280 mg; then, during dosing period II, administer a dose of approximately 70 mg every 6 weeks.
  • dosing period I administer twice at a dose of approximately 4.0 mg/kg per administration; then, during dosing period II, administer once every 6 weeks at a dose of approximately 1.0 mg/kg.
  • dosing period I administer twice a day at a dose of approximately 280 mg each time; then, during dosing period II, administer once every 6 weeks at a dose of approximately 70 mg.
  • the anti-CTLA-4 antibody is administered twice during dosing period I; and the time interval between the two administrations is ⁇ 4 weeks or ⁇ 6 weeks, for example, 4-20 weeks, 5-15 weeks, or 6-12 weeks.
  • the dosing regimen for the anti-PD-L1 antibody combined with the anti-CTLA-4 antibody is as follows:
  • the dose of anti-CTLA-4 antibody is 0.1-50 mg/kg, administered once or multiple times; and, (b) the dose of anti-PD-L1 antibody is 50-5000 mg, administered once every 3 weeks or once every 4 weeks.
  • the dose of anti-CTLA-4 antibody is 0.5-10 mg/kg, administered once or multiple times; and (b) the dose of anti-PD-L1 antibody is 50-5000 mg, administered once every 3 weeks or once every 4 weeks.
  • the dose of anti-CTLA-4 antibody is 5-1000 mg/kg, administered once or multiple times; and (b) the dose of anti-PD-L1 antibody is 50-5000 mg, administered once every 3 weeks or once every 4 weeks.
  • the dose of anti-CTLA-4 antibody is 100-400 mg/kg, administered once or multiple times; and (b) the dose of anti-PD-L1 antibody is 50-5000 mg, administered once every 3 weeks or once every 4 weeks.
  • the dosing regimen for the anti-PD-L1 antibody combined with the anti-CTLA-4 antibody is as follows:
  • the dose of anti-CTLA-4 antibody is 0.1-50 mg/kg, administered once or multiple times; and, (b) the dose of anti-PD-L1 antibody is 1-500 mg/kg, administered once every 3 weeks or once every 4 weeks.
  • the dose of anti-CTLA-4 antibody is 0.5-10 mg/kg, administered once or multiple times; and (b) the dose of anti-PD-L1 antibody is 1-500 mg/kg, administered once every 3 weeks or once every 4 weeks.
  • the dose of anti-CTLA-4 antibody is 5-1000 mg/kg, administered once or multiple times; and (b) the dose of anti-PD-L1 antibody is 1-500 mg/kg, administered once every 3 weeks or once every 4 weeks.
  • the dose of anti-CTLA-4 antibody is 100-400 mg/kg, administered once or multiple times; and (b) the dose of anti-PD-L1 antibody is 1-500 mg/kg, administered once every 3 weeks or once every 4 weeks.
  • the dosing regimen for the anti-PD-L1 antibody combined with the anti-CTLA-4 antibody is as follows:
  • the dose of anti-CTLA-4 antibody is 0.1-50 mg/kg, administered once or multiple times; and, (b) the dose of anti-PD-L1 antibody is about 1200 mg or about 1800 mg, administered once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody is administered at a dose of 0.5-10 mg/kg, once or multiple times; and (b) the anti-PD-L1 antibody is administered at a dose of about 1200 mg or about 1800 mg, once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody is administered at a dose of 5-1000 mg/kg, once or multiple times; and (b) the anti-PD-L1 antibody is administered at a dose of about 1200 mg or about 1800 mg, once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody is administered at a dose of 100-400 mg/kg, once or multiple times; and (b) the anti-PD-L1 antibody is administered at a dose of about 1200 mg or about 1800 mg, once every 3 weeks or once every 4 weeks.
  • the dosing regimen for the anti-PD-L1 antibody combined with the anti-CTLA-4 antibody is as follows:
  • the dose of anti-CTLA-4 antibody is 0.1-50 mg/kg, administered once or multiple times; and, (b) the dose of anti-PD-L1 antibody is about 20 mg/kg, administered once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody is administered at a dose of 0.5-10 mg/kg, once or multiple times; and (b) the anti-PD-L1 antibody is administered at a dose of approximately 20 mg/kg, once every 3 weeks or once every 4 weeks.
  • the dose of anti-CTLA-4 antibody is 5-1000 mg/kg, administered once or multiple times; and (b) the dose of anti-PD-L1 antibody is approximately 20 mg/kg, administered once every 3 weeks or once every 4 weeks.
  • the dose of anti-CTLA-4 antibody is 100-400 mg/kg, administered once or multiple times; and (b) the dose of anti-PD-L1 antibody is approximately 20 mg/kg, administered once every 3 weeks or once every 4 weeks.
  • the dosing regimen for the anti-PD-L1 antibody combined with the anti-CTLA-4 antibody is as follows:
  • the dose of anti-CTLA-4 antibody is 3.5-10 mg/kg, administered once or twice; and, (b) the dose of anti-PD-L1 antibody is about 1200 mg or about 1800 mg, administered once every 3 weeks or once every 4 weeks.
  • administer anti-CTLA-4 antibody at a dose of about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg or about 6 mg/kg, once or twice; and (b) administer anti-PD-L1 antibody at a dose of about 1200 mg or about 1800 mg, once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered at a dose of about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, or about 360 mg, once or twice; and (b) the anti-PD-L1 antibody may be administered at a dose of about 1200 mg or about 1800 mg, once every 3 weeks or once every 4 weeks.
  • administer anti-CTLA-4 antibody at a dose of 30-220 mg every 3 weeks, every 6 weeks, or every 9 weeks; and (b) administer anti-PD-L1 antibody at a dose of about 1200 mg or about 1800 mg every 3 weeks or every 4 weeks.
  • the anti-CTLA-4 antibody is administered at a dose of about 30 mg, about 50 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, or about 150 mg, once every 3 weeks, once every 6 weeks, or once every 9 weeks; and (b) the anti-PD-L1 antibody is administered at a dose of about 1200 mg or about 1800 mg, once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered at a dose of 0.5–3.5 mg/kg, once every 3 weeks, once every 6 weeks, or once every 9 weeks; and (b) the anti-PD-L1 antibody may be administered at a dose of about 1200 mg or about 1800 mg, once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered at a dose of about 0.5 mg/kg, about 1.0 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, or about 3.5 mg/kg, once every 3 weeks, once every 6 weeks, or once every 9 weeks; and (b) the anti-PD-L1 antibody may be administered at a dose of about 1200 mg or about 1800 mg, once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody is administered at a dose of 220-360 mg once or twice during dosing period I; the anti-CTLA-4 antibody is administered at a dose of 30-220 mg once every 3 weeks, once every 6 weeks, or once every 9 weeks during dosing period II; and (b) the anti-PD-L1 antibody is administered at a dose of about 1200 mg or about 1800 mg once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered once or twice at a dose of about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, or about 360 mg during administration period I; the anti-CTLA-4 antibody may be administered once or twice at a dose of about 30 mg, about 50 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, or about 150 mg during administration period II, once every 3 weeks, once every 6 weeks, or once every 9 weeks; and (b) the anti-PD-L1 antibody may be administered once every 3 weeks or once every 4 weeks at a dose of about 1200 mg or about 1800 mg.
  • the anti-CTLA-4 antibody is administered at a dose of 3.5–10 mg/kg during dosing period I, once or twice; the anti-CTLA-4 antibody is administered at a dose of 0.5–3.5 mg/kg during dosing period II, once every 3 weeks, once every 6 weeks, or once every 9 weeks; and (b) the anti-PD-L1 antibody is administered at a dose of about 1200 mg or about 1800 mg, once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered once or twice at a dose of about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg, or about 6 mg/kg during dosing period I; the anti-CTLA-4 antibody may be administered once or twice at a dose of about 0.5 mg/kg, about 1.0 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, or about 3.5 mg/kg during dosing period II, once every 3 weeks, once every 6 weeks, or once every 9 weeks; and (b) the anti-PD-L1 antibody may be administered at a dose of about 1200 mg or about 1800 mg, once every 3 weeks or once every 4 weeks.
  • the dosing regimen for the anti-PD-L1 antibody combined with the anti-CTLA-4 antibody is as follows:
  • the dose of anti-CTLA-4 antibody is 3.5-10 mg/kg, administered once or twice; and, (b) the dose of anti-PD-L1 antibody is about 20 mg/kg, administered once every 3 weeks or once every 4 weeks.
  • administer anti-CTLA-4 antibody at a dose of about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg or about 6 mg/kg, once or twice; and (b) administer anti-PD-L1 antibody at a dose of about 20 mg/kg, once every 3 weeks or once every 4 weeks.
  • the dose of anti-CTLA-4 antibody is 220-360 mg, administered once or twice; and, (b) the dose of anti-PD-L1 antibody is about 20 mg/kg, administered once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered at a dose of about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, or about 360 mg, once or twice; and (b) the anti-PD-L1 antibody may be administered at a dose of about 20 mg/kg, once every 3 weeks or once every 4 weeks.
  • the dose of anti-CTLA-4 antibody is 30-220 mg, administered once every 3 weeks, once every 6 weeks, or once every 9 weeks; and (b) the dose of anti-PD-L1 antibody is about 20 mg/kg, administered once every 3 weeks or once every 4 weeks.
  • administer anti-CTLA-4 antibody at a dose of about 30 mg, about 50 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, or about 150 mg every 3 weeks, every 6 weeks, or every 9 weeks; and (b) administer anti-PD-L1 antibody at a dose of about 20 mg/kg every 3 weeks or every 4 weeks.
  • the anti-CTLA-4 antibody may be administered at a dose of 0.5–3.5 mg/kg, once every 3 weeks, once every 6 weeks, or once every 9 weeks; and (b) the anti-PD-L1 antibody may be administered at a dose of approximately 20 mg/kg, once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered at a dose of about 0.5 mg/kg, about 1.0 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, or about 3.5 mg/kg, once every 3 weeks, once every 6 weeks, or once every 9 weeks; and (b) the anti-PD-L1 antibody may be administered at a dose of about 20 mg/kg, once every 3 weeks or once every 4 weeks.
  • the dose of anti-CTLA-4 antibody in dosing period I is 220-360 mg, administered once or twice; the dose of anti-CTLA-4 antibody in dosing period II is 30-220 mg, administered once every 3 weeks, once every 6 weeks, or once every 9 weeks; and (b) the dose of anti-PD-L1 antibody is approximately 20 mg/kg, administered once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered once or twice at a dose of about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, or about 360 mg during administration period I; the anti-CTLA-4 antibody may be administered once or twice at a dose of about 30 mg, about 50 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, or about 150 mg during administration period II, once every 3 weeks, once every 6 weeks, or once every 9 weeks; and (b) the anti-PD-L1 antibody may be administered at a dose of about 20 mg/kg, once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody is administered at a dose of 3.5–10 mg/kg during dosing period I, once or twice; the anti-CTLA-4 antibody is administered at a dose of 0.5–3.5 mg/kg during dosing period II, once every 3 weeks, once every 6 weeks, or once every 9 weeks; and (b) the anti-PD-L1 antibody is administered at a dose of approximately 20 mg/kg, once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered once or twice at a dose of about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg, or about 6 mg/kg during dosing period I; the anti-CTLA-4 antibody may be administered once or twice at a dose of about 0.5 mg/kg, about 1.0 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, or about 3.5 mg/kg during dosing period II, once every 3 weeks, once every 6 weeks, or once every 9 weeks; and (b) the anti-PD-L1 antibody may be administered at a dose of about 20 mg/kg, once every 3 weeks or once every 4 weeks.
  • the dosing regimen for the anti-PD-L1 antibody combined with the anti-CTLA-4 antibody is as follows:
  • the anti-CTLA-4 antibody is administered once or twice at a dose of 3.5-10 mg/kg/time;
  • the anti-CTLA-4 antibody is administered once every 6 weeks at a dose of 0.5-3.5 mg/kg; and
  • the anti-PD-L1 antibody is administered at a dose of 50-5000 mg once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody is administered once or twice at a dose of 220-360 mg/time;
  • the anti-CTLA-4 antibody is administered once every 6 weeks at a dose of 30-150 mg; and
  • the anti-PD-L1 antibody is administered at a dose of 50-5000 mg once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody is administered once or twice at a dose of 3.5-10 mg/kg per administration;
  • the anti-CTLA-4 antibody is administered once every 6 weeks at a dose of 0.5-3.5 mg/kg; and
  • the anti-PD-L1 antibody is administered at a dose of about 1200 mg or about 1800 mg, at a frequency of once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody is administered once or twice at a dose of about 3.5 mg/kg/time, about 4 mg/kg/time, about 4.5 mg/kg/time, about 5 mg/kg/time, about 5.5 mg/kg/time, about 6 mg/kg/time, or about 8 mg/kg/time;
  • the anti-CTLA-4 antibody is administered once every 6 weeks at a dose of 0.5 mg/kg, about 1.0 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, or about 3.5 mg/kg; and
  • the anti-PD-L1 antibody is administered at a dose of about 1200 mg or about 1800 mg, at a frequency of once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody is administered once or twice at a dose of 220-360 mg per administration;
  • the anti-CTLA-4 antibody is administered once every 6 weeks at a dose of 30-150 mg; and
  • the anti-PD-L1 antibody is administered at a dose of about 1200 mg or about 1800 mg once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody is administered once or twice at a dose of about 220 mg, about 240 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 320 mg, about 340 mg, or about 360 mg;
  • the anti-CTLA-4 antibody is administered once every 6 weeks at a dose of about 30 mg, about 50 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, or about 150 mg; and
  • the anti-PD-L1 antibody is administered at a dose of about 1200 mg or about 1800 mg, at a frequency of once every 3 weeks or once every 4 weeks.
  • the dosing regimen for the anti-PD-L1 antibody combined with the anti-CTLA-4 antibody is as follows:
  • the dosage of anti-CTLA-4 antibody is about 4.0 mg/kg or about 280 mg, administered once or twice; and the dosage of anti-PD-L1 antibody is about 1200 mg or about 1800 mg, administered once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered at a dose of approximately 1.0 mg/kg, once every 3 weeks, once every 6 weeks, or once every 9 weeks; and the anti-PD-L1 antibody may be administered at a dose of approximately 1200 mg or approximately 1800 mg, once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered once or twice at a dose of approximately 4.0 mg/kg per administration; then, during dosing period II, the anti-CTLA-4 antibody may be administered once every 6 weeks at a dose of approximately 1.0 mg/kg; and the anti-PD-L1 antibody may be administered at a dose of approximately 1200 mg or approximately 1800 mg, at a frequency of once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered once or twice at a dose of approximately 280 mg per dose; then, during dosing period II, the anti-CTLA-4 antibody may be administered once every 6 weeks at a dose of approximately 70 mg. And, the anti-PD-L1 antibody may be administered at a dose of approximately 1200 mg or approximately 1800 mg, at a frequency of once every 3 weeks or once every 4 weeks.
  • the dosing regimen for the anti-PD-L1 antibody combined with the anti-CTLA-4 antibody is as follows:
  • the dosage of the anti-CTLA-4 antibody is approximately 4.0 mg/kg or approximately 280 mg, administered once or twice; and the dosage of the anti-PD-L1 antibody is approximately 20 mg/kg, administered once every 3 weeks or once every 4 weeks.
  • the dose of anti-CTLA-4 antibody may be approximately 1.0 mg/kg, administered once every 3 weeks, once every 6 weeks, or once every 9 weeks; and the dose of anti-PD-L1 antibody may be approximately 20 mg/kg, administered once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered once or twice at a dose of approximately 4.0 mg/kg per administration; then, during dosing period II, the anti-CTLA-4 antibody may be administered once every 6 weeks at a dose of approximately 1.0 mg/kg; and the anti-PD-L1 antibody may be administered at a dose of approximately 20 mg/kg at a frequency of once every 3 weeks or once every 4 weeks.
  • the anti-CTLA-4 antibody may be administered once or twice at a dose of approximately 280 mg per dose; then, during dosing period II, the anti-CTLA-4 antibody may be administered once every 6 weeks at a dose of approximately 70 mg. And, the anti-PD-L1 antibody may be administered at a dose of approximately 20 mg/kg, at a frequency of once every 3 weeks or once every 4 weeks.
  • the dosing period I the interval between administration of the anti-CTLA-4 antibody, is 6-12 weeks.
  • the anti-CTLA-4 antibody is administered via intravenous injection.
  • ORR objective response rate
  • PFS progression-free survival
  • OS overall survival
  • the anti-PD-L1 antibody and anti-CTLA-4 antibody are further combined with chemotherapeutic agents, antibodies and/or antibody-drug conjugates with antitumor activity, and/or anti-angiogenic agents.
  • Anti-tumor activity refers to the cytotoxic activity and cell-killing effect on tumor cells, which can be confirmed by measuring the inhibitory activity against cell proliferation in vitro.
  • cancer cell lines that overexpress the target protein of antibodies or antibody-drug conjugates can be cultured, and various concentrations of antibodies or antibody-drug conjugates can be added to the culture system to measure the inhibitory activity against focus formation, colony formation, and spheroid growth.
  • Anti-tumor activity can also be confirmed in vivo, for example, by administering antibodies or antibody-drug conjugates to nude mice transplanted with tumor cell lines that overexpress the target protein, and measuring changes in cancer cells.
  • the chemotherapeutic agent is platinum-based chemotherapy based on tumor tissue typing. In some embodiments, the chemotherapeutic agent includes platinum-based drugs. In some embodiments, the chemotherapeutic agent includes platinum-based drugs and other chemotherapeutic agents.
  • the platinum-based drug is cisplatin and/or carboplatin.
  • chemotherapeutic agents include, but are not limited to, one or more of paclitaxel, albumin-bound paclitaxel, pemetrexed, and gemcitabine.
  • the chemotherapeutic agents include any combination of the following: 1) carboplatin or cisplatin, pemetrexed; 2) carboplatin or cisplatin, paclitaxel; 3) carboplatin or cisplatin, albumin-bound paclitaxel; 4) gemcitabine, and cisplatin.
  • the chemotherapeutic agents may be a combination of chemotherapeutic drugs known to those skilled in the art in tumor chemotherapy regimens.
  • the chemotherapeutic agents may be a combination of drugs in chemotherapy regimens recommended in the NCCN guidelines and CSCO guidelines.
  • the aforementioned chemotherapeutic agents are administered to the subjects according to the dosing regimens recommended in treatment guidelines (e.g., NCCN or CSCO).
  • the anti-angiogenic agent is an anti-VEGF antibody and/or an anti-VEGFR antibody.
  • the anti-angiogenic agent is bevacizumab.
  • the anti-VEGF antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:21-23, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:24-26.
  • VH heavy chain variable region
  • VL light chain variable region
  • the CDR described above is defined according to the Kabat, IMGT, Chothia, AbM, or Contact definition scheme. In some specific implementations, the CDR is defined according to the Kabat definition scheme.
  • the anti-VEGF antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL): wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:21-23, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:24-26.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-VEGF antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL): the VH comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:27, and the VL comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:28.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-VEGF antibody comprises any one, two, three, four, five, or six of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3.
  • the anti-VEGF antibody is a chimeric, humanized, fully human antibody or its antigen-binding fragment.
  • the anti-VEGF antibody includes a heavy chain variable region comprising an amino acid sequence as shown in SEQ ID NO:27, or an amino acid sequence having at least 80% or 90% sequence identity with it; and a light chain variable region comprising an amino acid sequence as shown in SEQ ID NO:28, or an amino acid sequence having at least 80% or 90% sequence identity with it.
  • the anti-VEGF antibody further comprises a heavy chain constant region and/or a light chain constant region.
  • the heavy chain constant region of the antibody constant region is selected from the human IgG1, IgG2, IgG3 and IgG4 constant regions and their variants;
  • the light chain constant region of the antibody constant region is selected from the human antibody ⁇ and ⁇ chain constant regions and their variants.
  • the anti-VEGF antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO:29 or having at least 80% or at least 90% sequence identity with it; and/or, the light chain comprises an amino acid sequence as shown in SEQ ID NO:30 or having at least 80% or at least 90% sequence identity with it.
  • the anti-VEGF antibody comprises a heavy chain with an amino acid sequence as shown in SEQ ID NO:29 and a light chain with an amino acid sequence as shown in SEQ ID NO:30.
  • the underlined portion is the variable region sequence of the antibody heavy or light chain
  • the ununderlined portion is the constant region sequence of the antibody.
  • the dosage of the anti-VEGF antibody is about 0.5 mg/kg to about 500 mg/kg, about 1 mg/kg to about 50 mg/kg, about 5 mg/kg to about 50 mg/kg, about 5 mg/kg to about 30 mg/kg, or about 10 mg/kg to about 30 mg/kg; about 1.0 mg/kg to about 30 mg/kg, about 2.0 mg/kg to about 30 mg/kg, about 8.0 mg/kg to about 30 mg/kg, about 10 mg/kg to about 30 mg/kg, about 1.0 mg/kg to about 20 mg/kg, about 2.0 mg/kg to about 20 mg/kg, about 8.0 mg/kg to about 20 mg/kg, about 10 mg/kg to about 20 mg/kg; or any range between these values.
  • the dosage of the anti-VEGF antibody is selected from about 2.0 mg/kg, about 3.0 mg/kg, about 4.0 mg/kg, about 5.0 mg/kg, about 6.0 mg/kg, about 6.5 mg/kg, about 7.0 mg/kg, about 7.5 mg/kg, 8.0 mg/kg, 8.5 mg/kg, about 9.0 mg/kg, about 9.5 mg/kg, about 10.0 mg/kg, about 10.5 mg/kg, about 11.0 mg/kg, about 11.5 mg/kg, about 12.0 mg/kg, about 12.5 mg/kg, about 13.0 mg/kg, about 13.5 mg/kg, about 14.0 mg/kg, about 14.5 mg/kg, about 15.0 mg/kg, about 15.5 mg/kg, about 16.0 mg/kg, about 16.5 mg/kg.
  • g/kg approximately 17.0 mg/kg, approximately 18.0 mg/kg, approximately 19.0 mg/kg, approximately 20.0 mg/kg, approximately 21.0 mg/kg, approximately 22.0 mg/kg, approximately 23.0 mg/kg, approximately 24.0 mg/kg, approximately 25.0 mg/kg, approximately 30.0 mg/kg, approximately 35 mg/kg, approximately 40 mg/kg, approximately 45 mg/kg, approximately 50 mg/kg, approximately 55 mg/kg, approximately 60 mg/kg, approximately 65 mg/kg, approximately 70 mg/kg, approximately 75 mg/kg, approximately 80 mg/kg, approximately 85 mg/kg, approximately 90 mg/kg, approximately 95 mg/kg, approximately 110 mg/kg, approximately 120 mg/kg, approximately 130 mg/kg, approximately 140 mg/kg, approximately 150 mg/kg, approximately 200 mg/kg. Or any range of values between these points.
  • the anti-VEGF antibody is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, or once every twelve weeks. In some specific embodiments, the anti-VEGF antibody-drug conjugate is administered once every three weeks.
  • the dosing regimen of anti-PD-L1 antibody combined with anti-CTLA-4 antibody is selected from:
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (4 mg/kg, once administered at C1 and once administered at C5), and platinum-based chemotherapy based on tumor tissue typing;
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (280 mg, once administered at C1 and once administered at C5), and platinum-based chemotherapy based on tumor tissue typing;
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (280 mg, once administered at C1), and platinum-based chemotherapy based on tumor tissue typing;
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (1 mg/kg, Q6W), and platinum-based chemotherapy based on tumor tissue typing;
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (C1 is administered once or twice, 4 mg/kg/time; C5 is started with 1 mg/kg, Q6W continuously), and platinum-based chemotherapy based on tumor tissue typing;
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (C1 administration once or twice, 280 mg/time; C5 onwards, 70 mg, Q6W), and platinum-based chemotherapy based on tumor tissue typing.
  • a treatment cycle may be 2 weeks, 3 weeks, or 4 weeks, with C1 being the first treatment cycle and C5 being the fifth treatment cycle.
  • a treatment cycle may be 3 weeks.
  • Anti-PD-L1 antibody (1200 mg, Q3W), anti-CTLA-4 antibody (4 mg/kg, once administered at C1 and once administered at C5), and platinum-based chemotherapy based on tumor tissue typing;
  • Anti-PD-L1 antibody (1200 mg, Q3W), anti-CTLA-4 antibody (280 mg, once administered at C1 and once administered at C5), and platinum-based chemotherapy based on tumor tissue typing;
  • Anti-PD-L1 antibody (1200 mg, Q3W), anti-CTLA-4 antibody (4 mg/kg, once administered at C1), and platinum-based chemotherapy based on tumor tissue typing;
  • Anti-PD-L1 antibody (1800 mg, Q4W), anti-CTLA-4 antibody (280 mg, once administered at C1 and once administered at C5), and platinum-based chemotherapy based on tumor tissue typing;
  • Anti-PD-L1 antibody (1800 mg, Q4W), anti-CTLA-4 antibody (1 mg/kg, Q6W), and platinum-based chemotherapy based on tumor tissue typing;
  • the dosing regimen of anti-PD-L1 antibody combined with anti-CTLA-4 antibody is selected from:
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (C1 is administered once or twice, 280 mg/time; C5 is administered continuously at 70 mg, Q6W).
  • the dosing regimen of anti-PD-L1 antibody combined with anti-CTLA-4 antibody is selected from:
  • Anti-PD-L1 antibody (1200mg, Q3W), anti-CTLA-4 antibody (4mg/kg, administered once at C1 and once at C5);
  • Anti-PD-L1 antibody (1200mg, Q3W), anti-CTLA-4 antibody (280mg, administered once at C1 and once at C5);
  • Anti-PD-L1 antibody (1200mg, Q3W), anti-CTLA-4 antibody (C1 is administered once or twice, 4mg/kg/time; C5 onwards, 1mg/kg, Q6W is administered continuously);
  • Anti-PD-L1 antibody (1200 mg, Q3W), anti-CTLA-4 antibody (C1 is administered once or twice, 280 mg/time; C5 is started with 70 mg, Q6W).
  • the dosing regimen of anti-PD-L1 antibody combined with anti-CTLA-4 antibody is selected from:
  • Anti-PD-L1 antibody (1800mg, Q4W), anti-CTLA-4 antibody (4mg/kg, administered once at C1 and once at C5);
  • Anti-PD-L1 antibody (1800 mg, Q4W), anti-CTLA-4 antibody (280 mg, administered once at C1 and once at C5);
  • Anti-PD-L1 antibody (1800mg, Q4W), anti-CTLA-4 antibody (4mg/kg, administered once at C1);
  • Anti-PD-L1 antibody (1800 mg, Q4W), anti-CTLA-4 antibody (280 mg, once administered at C1);
  • Anti-PD-L1 antibody (1800mg, Q4W), anti-CTLA-4 antibody (1mg/kg, Q6W);
  • Anti-PD-L1 antibody (1800mg, Q4W), anti-CTLA-4 antibody (C1 is administered once or twice, 4mg/kg/time; C5 is started with 1mg/kg, Q6W continuously);
  • Anti-PD-L1 antibody (1800 mg, Q4W), anti-CTLA-4 antibody (C1 is administered once or twice, 280 mg/time; C5 is started with 70 mg, Q6W).
  • the dosing regimen of anti-PD-L1 antibody combined with anti-CTLA-4 antibody and anti-VEGF antibody is selected from:
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (4 mg/kg, once at C1 and once at C5), anti-VEGF antibody (15 mg/kg, Q3W);
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (280 mg, administered once at C1 and once at C5), anti-VEGF antibody (15 mg/kg, Q3W);
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (4 mg/kg, C1 administration once), anti-VEGF antibody (15 mg/kg, Q3W);
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (280 mg, administered once at C1);
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (1 mg/kg, Q6W), anti-VEGF antibody (15 mg/kg, Q3W);
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (C1 is administered once or twice, 4 mg/kg/time; C5 is started with 1 mg/kg, Q6W continuously), anti-VEGF antibody (15 mg/kg, Q3W);
  • Anti-PD-L1 antibody (20 mg/kg, Q3W), anti-CTLA-4 antibody (C1 is administered once or twice, 280 mg/time; C5 is administered continuously at 70 mg, Q6W), anti-VEGF antibody (15 mg/kg, Q3W).
  • the dosing regimen of anti-PD-L1 antibody combined with anti-CTLA-4 antibody and anti-VEGF antibody is selected from:
  • Anti-PD-L1 antibody (1200mg, Q3W), anti-CTLA-4 antibody (4mg/kg, once administered at C1 and once administered at C5), anti-VEGF antibody (15mg/kg, Q3W);
  • Anti-PD-L1 antibody (1200mg, Q3W), anti-CTLA-4 antibody (280mg, administered once at C1 and once at C5), anti-VEGF antibody (15mg/kg, Q3W);
  • Anti-PD-L1 antibody (1200mg, Q3W), anti-CTLA-4 antibody (4mg/kg, C1 administration once), anti-VEGF antibody (15mg/kg, Q3W);
  • Anti-PD-L1 antibody (1200 mg, Q3W), anti-CTLA-4 antibody (280 mg, once administered at C1);
  • Anti-PD-L1 antibody (1200mg, Q3W), anti-CTLA-4 antibody (1mg/kg, Q6W), anti-VEGF antibody (15mg/kg, Q3W);
  • Anti-PD-L1 antibody (1200mg, Q3W), anti-CTLA-4 antibody (C1 is administered once or twice, 4mg/kg/time; C5 is administered continuously at 1mg/kg, Q6W), anti-VEGF antibody (15mg/kg, Q3W);
  • Anti-PD-L1 antibody (1200 mg, Q3W), anti-CTLA-4 antibody (C1 is administered once or twice, 280 mg/time; C5 is administered continuously at 70 mg, Q6W), anti-VEGF antibody (15 mg/kg, Q3W).
  • the dosing regimen of anti-PD-L1 antibody combined with anti-CTLA-4 antibody and anti-VEGF antibody is selected from:
  • Anti-PD-L1 antibody (1800 mg/kg, Q4W), anti-CTLA-4 antibody (4 mg/kg, once at C1 and once at C5), anti-VEGF antibody (15 mg/kg, Q3W);
  • Anti-PD-L1 antibody (1800 mg/kg, Q4W), anti-CTLA-4 antibody (280 mg, once at C1 and once at C5), anti-VEGF antibody (15 mg/kg, Q3W);
  • Anti-PD-L1 antibody (1800 mg/kg, Q4W), anti-CTLA-4 antibody (4 mg/kg, C1 administration once), anti-VEGF antibody (15 mg/kg, Q3W);
  • Anti-PD-L1 antibody (1800 mg/kg, Q4W), anti-CTLA-4 antibody (280 mg, administered once at C1);
  • Anti-PD-L1 antibody (1800 mg/kg, Q4W), anti-CTLA-4 antibody (1 mg/kg, Q6W), anti-VEGF antibody (15 mg/kg, Q3W);
  • Anti-PD-L1 antibody (1800 mg/kg, Q4W), anti-CTLA-4 antibody (C1 is administered once or twice, 4 mg/kg/time; C5 is administered continuously at 1 mg/kg, Q6W), anti-VEGF antibody (15 mg/kg, Q3W);
  • Anti-PD-L1 antibody (1800 mg/kg, Q4W), anti-CTLA-4 antibody (C1 is administered once or twice, 280 mg/time; C5 is administered continuously at 70 mg, Q6W), anti-VEGF antibody (15 mg/kg, Q3W).
  • the anti-CTLA-4 antibody and anti-PD-L1 antibody are combined with a chemotherapeutic agent.
  • the chemotherapeutic agent is selected from pyrimidine antitumor drugs and/or platinum-based drugs; in some embodiments, the pyrimidine antitumor drug is selected from gemcitabine, and the platinum-based drug is selected from cisplatin, carboplatin, nedaplatin, oxaliplatin, or lobaplatin; in some specific embodiments, the platinum-based drug is selected from cisplatin and/or carboplatin.
  • the dosage of gemcitabine is selected from about 50-2000 mg/ m2 , about 100-1500 mg/ m2 , about 400 mg/ m2 , about 500 mg/ m2 , about 600 mg/ m2 , about 700 mg/ m2 , about 800 mg/ m2 , about 900 mg/ m2 , about 1000 mg/ m2 , about 1100 mg/ m2 , about 1200 mg/ m2 , about 1300 mg/ m2 , and about 1400 mg/ m2 .
  • the dosage of gemcitabine is selected from about 900 mg/ m2 , about 910 mg/ m2 , about 920 mg/ m2 , about 930 mg/ m2 , about 940 mg/ m2 , about 950 mg/ m2 , about 960 mg/ m2 , about 970 mg/ m2 , about 980 mg/ m2 , about 990 mg/ m2 , about 1000 mg/ m2 , about 1100 mg/ m2 , about 1200 mg/ m2 , about 1300 mg/ m2 , about 1400 mg/ m2 , about 1500 mg/ m2 , about 1600 mg/ m2 , about 1700 mg/ m2 , about 1800 mg/ m2 , and about 1900 mg/ m2. Approximately 2000 mg/ m2 , or any range between the two mentioned above.
  • gemcitabine is administered once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some specific embodiments, gemcitabine is administered once every 3 weeks.
  • the gemcitabine is administered at doses of approximately 950 mg/ m2 , approximately 960 mg/ m2 , approximately 970 mg/ m2 , approximately 980 mg/ m2 , approximately 990 mg/ m2 , approximately 1000 mg/ m2 , approximately 1100 mg/ m2 , approximately 1200 mg/ m2 , approximately 1300 mg/ m2 , approximately 1400 mg/ m2 , or approximately 1500 mg/ m2 , at frequencies of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks.
  • the gemcitabine is administered at a dose of about 950-1500 mg/ m2 , and at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks.
  • the gemcitabine is administered at a dose of about 960-1400 mg/ m2 , and at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks.
  • the gemcitabine is administered at a dose of about 980-1200 mg/ m2 , and at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks.
  • the gemcitabine is administered at a dose of approximately 980-1200 mg/ m2 , once every 3 weeks.
  • the gemcitabine is administered at a dose of approximately 980 mg/ m2 , once every 3 weeks.
  • the gemcitabine is administered at a dose of approximately 990 mg/ m2 , once every 3 weeks.
  • the gemcitabine is administered at a dose of approximately 1000 mg/ m2 , once every 3 weeks.
  • the gemcitabine is administered at a dose of approximately 1100 mg/ m2 , once every 3 weeks.
  • the gemcitabine is administered at a dose of approximately 1200 mg/ m2 , once every 3 weeks.
  • gemcitabine can be administered orally, parenterally, or transdermally, with parenterial administration including but not limited to intravenous injection, subcutaneous injection, and intramuscular injection. In some specific embodiments, gemcitabine is administered via intravenous injection.
  • the dosage of cisplatin is about 1-100 mg/ m2 , about 5-80 mg/ m2 , about 5-70 mg/ m2 , about 5-60 mg/ m2 , or about 5-50 mg/ m2 .
  • the dosage of cisplatin is about 5 mg/ m2 , about 15 mg/ m2 , about 20 mg/ m2 , about 25 mg/ m2 , about 30 mg/ m2 , about 35 mg/ m2 , about 40 mg/ m2 , about 45 mg/ m2 , about 50 mg/ m2 ; or any range between any two of the foregoing.
  • the cisplatin is administered once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some specific embodiments, the cisplatin is administered once every 3 weeks.
  • the cisplatin is administered at a dose of about 1-100 mg/ m2 , and at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some specific embodiments, the cisplatin is administered at a dose of about 1-100 mg/ m2 , and at a frequency of once every 3 weeks.
  • the cisplatin is administered at a dose of about 5-80 mg/ m2 , and at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some specific embodiments, the cisplatin is administered at a dose of about 5-80 mg/ m2 , and at a frequency of once every 3 weeks.
  • the cisplatin is administered at a dose of about 5-70 mg/ m2 , and at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some specific embodiments, the cisplatin is administered at a dose of about 5-70 mg/ m2 , and at a frequency of once every 3 weeks.
  • the cisplatin is administered at a dose of about 5-60 mg/ m2 , and at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some specific embodiments, the cisplatin is administered at a dose of about 5-60 mg/ m2 , and at a frequency of once every 3 weeks.
  • the cisplatin is administered at a dose of about 5-50 mg/ m2 , and at a frequency of once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some specific embodiments, the cisplatin is administered at a dose of about 5-50 mg/ m2 , and at a frequency of once every 3 weeks.
  • the cisplatin is administered at a dose of about 20 mg/ m2 , about 21 mg/ m2 , about 22 mg/ m2 , about 23 mg/ m2 , about 24 mg/ m2 , about 25 mg/ m2 , about 26 mg/ m2 , about 27 mg/ m2 , about 28 mg/ m2 , about 29 mg/ m2 , or about 30 mg/ m2 ; and at a frequency of once every 3 weeks.
  • cisplatin can be administered orally, parenterally, or transdermally, with parenterial administration including but not limited to intravenous injection, subcutaneous injection, and intramuscular injection. In some specific embodiments, cisplatin is administered via intravenous injection.
  • the dosing regimen of the anti-CTLA-4 antibody combined with the anti-PD-L1 antibody is any of the following:
  • the anti-CTLA-4 antibody is administered using a variable dosing cycle.
  • a first dose of the anti-CTLA-4 antibody is administered during the first treatment cycle (i.e., dosing period I), and a second dose of the anti-CTLA-4 antibody is administered during the second treatment cycle (i.e., dosing period II).
  • the first dose of the anti-CTLA-4 antibody is approximately 60-500 mg, and the second dose is approximately 1-150 mg.
  • the dosage of the anti-PD-L1 antibody is approximately 50-2000 mg, and the dosing frequency is once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, or at least once every 10 weeks.
  • the anti-CTLA-4 antibody is administered using a variable dosing cycle.
  • the first treatment cycle administers a first dose of the anti-CTLA-4 antibody
  • the second treatment cycle administers a second dose of the anti-CTLA-4 antibody.
  • the first dose of the anti-CTLA-4 antibody is approximately 100-460 mg
  • the second dose is approximately 20-130 mg.
  • the dosage of the anti-PD-L1 antibody is approximately 100-2000 mg, and the dosing frequency is once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, or at least once every 10 weeks.
  • the anti-CTLA-4 antibody is administered using a variable dosing cycle.
  • the first treatment cycle administers a first dose of the anti-CTLA-4 antibody
  • the second treatment cycle administers a second dose of the anti-CTLA-4 antibody.
  • the first dose of the anti-CTLA-4 antibody is approximately 160-400 mg
  • the second dose is approximately 30-120 mg.
  • the dosage of the anti-PD-L1 antibody is approximately 200-2000 mg, and the dosing frequency is once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, or at least once every 10 weeks.
  • the anti-CTLA-4 antibody is administered using a variable dosing cycle.
  • the first treatment cycle administers a first dose of the anti-CTLA-4 antibody
  • the second treatment cycle administers a second dose of the anti-CTLA-4 antibody.
  • the first dose of the anti-CTLA-4 antibody is approximately 180-380 mg
  • the second dose is approximately 50-100 mg.
  • the dosage of the anti-PD-L1 antibody is approximately 300-2000 mg, and the dosing frequency is once every 3 weeks;
  • the anti-CTLA-4 antibody is administered in a variable dosing cycle, with a first dose of the anti-CTLA-4 antibody administered in the first treatment cycle and a second dose of the anti-CTLA-4 antibody administered in the second treatment cycle; the first dose of the anti-CTLA-4 antibody is approximately 200-360 mg, and the second dose of the anti-CTLA-4 antibody is approximately 60-90 mg; and,
  • the dosage of the anti-PD-L1 antibody is approximately 400-2000 mg, and the dosing frequency is once every 3 weeks;
  • the anti-CTLA-4 antibody is administered in a variable dosing cycle, with a first dose of the anti-CTLA-4 antibody administered in the first treatment cycle and a second dose of the anti-CTLA-4 antibody administered in the second treatment cycle;
  • the first dose of the anti-CTLA-4 antibody is approximately 200 mg, approximately 220 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, or approximately 360 mg
  • the second dose of the anti-CTLA-4 antibody is approximately 60 mg, approximately 70 mg, approximately 80 mg, or approximately 90 mg;
  • the dosage of the anti-PD-L1 antibody is approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, approximately 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg, approximately 1350 mg, approximately 1400 mg, approximately 1450 mg, approximately 1500 mg, approximately 1550 mg, and approximately 1600 mg, and the dosing frequency is once every 3 weeks;
  • the anti-CTLA-4 antibody is administered in a variable dosing cycle, with a first dose of the anti-CTLA-4 antibody administered in the first treatment cycle and a second dose of the anti-CTLA-4 antibody administered in the second treatment cycle;
  • the first dose of the anti-CTLA-4 antibody is approximately 260 mg, approximately 265 mg, approximately 270 mg, approximately 275 mg, approximately 280 mg, approximately 285 mg, approximately 290 mg, approximately 295 mg, and approximately 300 mg;
  • the second dose of the anti-CTLA-4 antibody is approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, and approximately 90 mg; and,
  • the dosage of the anti-PD-L1 antibody is approximately 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg, approximately 1350 mg, and approximately 1400 mg, and the dosing frequency is once every 3 weeks.
  • the first treatment cycle of the anti-CTLA-4 antibody is 12 weeks, with a first dose of approximately 260 mg, approximately 265 mg, approximately 270 mg, approximately 275 mg, approximately 280 mg, approximately 285 mg, approximately 290 mg, approximately 295 mg, and approximately 300 mg of anti-CTLA-4 antibody administered on the first day of the treatment cycle.
  • a second dose of approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, and approximately 90 mg of anti-CTLA-4 antibody is administered every 6 weeks; and,
  • the dosage of the anti-PD-L1 antibody is approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, and approximately 1300 mg, and the dosing frequency is once every 3 weeks;
  • the first treatment cycle of the anti-CTLA-4 antibody is 12 weeks, with a first dose of approximately 270 mg, approximately 275 mg, approximately 280 mg, approximately 285 mg, and approximately 290 mg of anti-CTLA-4 antibody administered on the first day of the treatment cycle.
  • a second dose of approximately 65 mg, approximately 70 mg, and approximately 75 mg of anti-CTLA-4 antibody is administered every 6 weeks; and,
  • the dosage of the anti-PD-L1 antibody is approximately 1150 mg, approximately 1200 mg, and approximately 1250 mg, and the dosing frequency is once every 3 weeks;
  • the first treatment cycle of the anti-CTLA-4 antibody is 12 weeks, with a first dose of approximately 280 mg of the anti-CTLA-4 antibody administered on the first day of the treatment cycle, and a second dose of approximately 70 mg of the anti-CTLA-4 antibody administered every 6 weeks in the second treatment cycle; and,
  • the dosage of the anti-PD-L1 antibody is approximately 1180 mg, approximately 1200 mg, and approximately 1220 mg, and the dosing frequency is once every 3 weeks.
  • the dosing regimen of anti-CTLA-4 antibody combined with anti-PD-L1 antibody, gemcitabine, and cisplatin is any one of the following:
  • the anti-CTLA-4 antibody is administered in a variable dosing cycle, with a first dose of the anti-CTLA-4 antibody administered in the first treatment cycle and a second dose of the anti-CTLA-4 antibody administered in the second treatment cycle; the first dose of the anti-CTLA-4 antibody is approximately 60-500 mg, and the second dose of the anti-CTLA-4 antibody is approximately 1-150 mg; and,
  • the dosage of the anti-PD-L1 antibody is approximately 50-2000 mg, and the dosing frequency is once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, or at least once every 10 weeks.
  • the dosage of gemcitabine is selected from about 50-2000 mg/ m2 , and the dosing frequency is once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, or at least once every 10 weeks.
  • the dosage of cisplatin is about 1-100 mg/ m2 , and the frequency of administration is once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, or at least once every 10 weeks.
  • the anti-CTLA-4 antibody is administered using a variable dosing cycle.
  • the first treatment cycle administers a first dose of the anti-CTLA-4 antibody
  • the second treatment cycle administers a second dose of the anti-CTLA-4 antibody.
  • the first dose of the anti-CTLA-4 antibody is approximately 100-460 mg
  • the second dose is approximately 20-130 mg.
  • the dosage of the anti-PD-L1 antibody is approximately 100-2000 mg, and the dosing frequency is once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, or at least once every 10 weeks.
  • the dosage of gemcitabine is selected from about 950-1500 mg/ m2 , and the dosing frequency is once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, or at least once every 10 weeks.
  • the dosage of cisplatin is approximately 5-80 mg/ m2 , and the frequency of administration is once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, or at least once every 10 weeks.
  • the anti-CTLA-4 antibody is administered using a variable dosing cycle.
  • the first treatment cycle administers a first dose of the anti-CTLA-4 antibody
  • the second treatment cycle administers a second dose of the anti-CTLA-4 antibody.
  • the first dose of the anti-CTLA-4 antibody is approximately 160-400 mg
  • the second dose is approximately 30-120 mg.
  • the dosage of the anti-PD-L1 antibody is approximately 200-2000 mg, and the dosing frequency is once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, or at least once every 10 weeks.
  • the dosage of gemcitabine is selected from about 960-1400 mg/ m2 , and the dosing frequency is once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, or at least once every 10 weeks.
  • the dosage of cisplatin is approximately 5-70 mg/ m2 , and the frequency of administration is once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, or at least once every 10 weeks.
  • the anti-CTLA-4 antibody is administered using a variable dosing cycle.
  • the first treatment cycle administers a first dose of the anti-CTLA-4 antibody
  • the second treatment cycle administers a second dose of the anti-CTLA-4 antibody.
  • the first dose of the anti-CTLA-4 antibody is approximately 180-380 mg
  • the second dose is approximately 50-100 mg.
  • the dosage of the anti-PD-L1 antibody is approximately 300-2000 mg, and the dosing frequency is once every 3 weeks;
  • the dosage of gemcitabine is selected from approximately 960-1400 mg/ m2 , and the dosing frequency is once every 3 weeks;
  • the dosage of cisplatin is approximately 5-60 mg/ m2 , and the dosing frequency is once every 3 weeks;
  • the anti-CTLA-4 antibody is administered in a variable dosing cycle, with a first dose of the anti-CTLA-4 antibody administered in the first treatment cycle and a second dose of the anti-CTLA-4 antibody administered in the second treatment cycle; the first dose of the anti-CTLA-4 antibody is approximately 200-360 mg, and the second dose of the anti-CTLA-4 antibody is approximately 60-90 mg; and,
  • the dosage of the anti-PD-L1 antibody is approximately 400-2000 mg, and the dosing frequency is once every 3 weeks;
  • the dosage of gemcitabine is selected from approximately 980-1200 mg/ m2 , and the dosing frequency is once every 3 weeks;
  • the dosage of cisplatin is approximately 5-50 mg/ m2 , and the dosing frequency is once every 3 weeks;
  • the anti-CTLA-4 antibody is administered in a variable dosing cycle, with a first dose of the anti-CTLA-4 antibody administered in the first treatment cycle and a second dose of the anti-CTLA-4 antibody administered in the second treatment cycle;
  • the first dose of the anti-CTLA-4 antibody is approximately 200 mg, approximately 220 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, or approximately 360 mg
  • the second dose of the anti-CTLA-4 antibody is approximately 60 mg, approximately 70 mg, approximately 80 mg, or approximately 90 mg;
  • the dosage of the anti-PD-L1 antibody is approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, approximately 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg, approximately 1350 mg, approximately 1400 mg, approximately 1450 mg, approximately 1500 mg, approximately 1550 mg, and approximately 1600 mg, and the dosing frequency is once every 3 weeks;
  • the recommended dosage of gemcitabine is selected from approximately 900 mg/ m2 , 910 mg/ m2 , 920 mg/ m2 , 930 mg/ m2 , 940 mg/ m2 , 950 mg/ m2 , 960 mg/ m2 , 970 mg/ m2 , 980 mg/ m2 , 990 mg/ m2 , 1000 mg/ m2 , 1100 mg/ m2 , 1200 mg/ m2 , 1300 mg/ m2 , 1400 mg/ m2 , 1500 mg/ m2 , 1600 mg/ m2 , 1700 mg/ m2 , 1800 mg/ m2 , and 1900 mg/ m2. Approximately 2000 mg/ m2 , administered once every 3 weeks;
  • the dosage of cisplatin is approximately 5 mg/ m2 , approximately 15 mg/ m2 , approximately 20 mg/ m2 , approximately 25 mg/ m2 , approximately 30 mg/ m2 , approximately 35 mg/ m2 , approximately 40 mg/ m2 , approximately 45 mg/ m2 , and approximately 50 mg/ m2 , administered once every 3 weeks.
  • the anti-CTLA-4 antibody is administered in a variable dosing cycle, with a first dose of the anti-CTLA-4 antibody administered in the first treatment cycle and a second dose of the anti-CTLA-4 antibody administered in the second treatment cycle;
  • the first dose of the anti-CTLA-4 antibody is approximately 260 mg, approximately 265 mg, approximately 270 mg, approximately 275 mg, approximately 280 mg, approximately 285 mg, approximately 290 mg, approximately 295 mg, and approximately 300 mg;
  • the second dose of the anti-CTLA-4 antibody is approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, and approximately 90 mg; and,
  • the dosage of the anti-PD-L1 antibody is approximately 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg, approximately 1350 mg, and approximately 1400 mg, and the dosing frequency is once every 3 weeks.
  • the dosage of gemcitabine is selected from approximately 950 mg/ m2 , approximately 960 mg/ m2 , approximately 970 mg/ m2 , approximately 980 mg/ m2 , approximately 990 mg/ m2 , approximately 1000 mg/ m2 , approximately 1100 mg/ m2 , approximately 1200 mg/ m2 , approximately 1300 mg/ m2 , approximately 1400 mg/ m2 , and approximately 1500 mg/ m2 , and the dosing frequency is once every 3 weeks;
  • the dosage of cisplatin is approximately 10 mg/ m2 , approximately 15 mg/ m2 , approximately 20 mg/ m2 , approximately 25 mg/ m2 , approximately 30 mg/ m2 , approximately 35 mg/ m2 , and approximately 40 mg/ m2 , and the dosing frequency is once every 3 weeks;
  • the first treatment cycle of the anti-CTLA-4 antibody is 12 weeks, with a first dose of 260 mg, approximately 265 mg, approximately 270 mg, approximately 275 mg, approximately 280 mg, approximately 285 mg, approximately 290 mg, approximately 295 mg, and approximately 300 mg of anti-CTLA-4 antibody administered on the first day of the treatment cycle.
  • a second dose of approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, and approximately 90 mg of anti-CTLA-4 antibody is administered every 6 weeks; and,
  • the dosage of the anti-PD-L1 antibody is approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, and approximately 1300 mg, and the dosing frequency is once every 3 weeks;
  • the dosage of gemcitabine is selected from approximately 980 mg/ m2 , approximately 990 mg/ m2 , approximately 1000 mg/ m2 , approximately 1100 mg/ m2 , and approximately 1200 mg/ m2 , and the dosing frequency is once every 3 weeks;
  • the dosage of cisplatin is approximately 15 mg/ m2 , approximately 20 mg/ m2 , approximately 25 mg/ m2 , approximately 30 mg/ m2 , and approximately 35 mg/ m2 , and the dosing frequency is once every 3 weeks;
  • the first treatment cycle of the anti-CTLA-4 antibody is 12 weeks, with a first dose of approximately 270 mg, approximately 275 mg, approximately 280 mg, approximately 285 mg, and approximately 290 mg of anti-CTLA-4 antibody administered on the first day of the treatment cycle.
  • a second dose of approximately 65 mg, approximately 70 mg, and approximately 75 mg of anti-CTLA-4 antibody is administered every 6 weeks; and,
  • the dosage of the anti-PD-L1 antibody is approximately 1150 mg, approximately 1200 mg, and approximately 1250 mg, and the dosing frequency is once every 3 weeks;
  • the dosage of gemcitabine is selected from approximately 990 mg/ m2 , approximately 1000 mg/ m2 , and approximately 1100 mg/ m2 , and the dosing frequency is once every 3 weeks;
  • the cisplatin was administered at doses of approximately 20 mg/ m2 , approximately 25 mg/ m2 , and approximately 30 mg/ m2 , at a frequency of once every 3 weeks.
  • the first treatment cycle of the anti-CTLA-4 antibody is 12 weeks, with a first dose of approximately 280 mg of the anti-CTLA-4 antibody administered on the first day of the treatment cycle, and a second dose of approximately 70 mg of the anti-CTLA-4 antibody administered every 6 weeks in the second treatment cycle; and,
  • the dosage of the anti-PD-L1 antibody is approximately 1180 mg, approximately 1200 mg, and approximately 1220 mg, and the dosing frequency is once every 3 weeks;
  • the dosage of gemcitabine is selected from approximately 995 mg/ m2 , approximately 1000 mg/ m2 , and approximately 1005 mg/ m2 , and the dosing frequency is once every 3 weeks;
  • the cisplatin was administered at doses of approximately 23 mg/ m2 , 24 mg/ m2 , 25 mg/ m2 , 26 mg/ m2 , and 27 mg/ m2 , at a frequency of once every 3 weeks.
  • the anti-CTLA-4 antibody of this disclosure is used to treat biliary adenocarcinoma, demonstrating good safety and positive antitumor activity. It exhibits a high objective response rate, a reduced incidence of adverse reactions, good clinical tolerability, and effectively improves patient survival time.
  • tumor subjects receiving the treatment regimens of this disclosure have significantly improved ORR, DoR, DCR, PFS, and/or OS.
  • ORR is defined as the proportion of subjects who achieve a CR or PR according to RECIST v1.1. If a CR or PR is achieved, the subject must confirm the outcome at least 4 weeks (28 days) after the initial evaluation.
  • Best overall response refers to the best response as assessed by the investigator, which is the best response recorded from the randomization date to the date on which disease progression is objectively recorded according to RECIST v1.1 or to the date on which a new anti-tumor therapy is started (whichever occurs first).
  • DoR is defined as the date from the first recorded tumor remission (as assessed by RECIST v1.1) to the date of the first recorded disease progression or death from any cause, whichever occurs first.
  • DCR is defined as the proportion of subjects who, according to RECIST v1.1, achieved the best overall response of CR, PR, and SD.
  • PFS is defined as the date from a randomized date to the date on which tumor progression (as assessed by RECIST v 1.1, regardless of whether treatment was continued) was first recorded or the date of death from any cause, whichever occurs first.
  • OS is defined as the time from the randomization date to the subject's death for any reason. For subjects still alive at the last follow-up, their OS is calculated from the last follow-up date as data censored. For subjects lost to follow-up, their OS is calculated from the last confirmed survival time before loss to follow-up as data censored.
  • the OS of data censoring is defined as the time from randomization to censoring.
  • Figure 1 shows the remission of tumor lesions under different dosing regimens in Example 2.
  • this disclosure defines the following:
  • antibody-drug conjugate refers to a complex in which a cytotoxic drug is bound to an antibody via a linker.
  • the cytotoxic drug used in this disclosure is any compound that has antitumor effects and contains substituents or a portion of the structure that can be linked to the linker; there are no particular limitations.
  • part or all of the linker is cleaved within tumor cells, releasing the antitumor compound portion, thereby exhibiting an antitumor effect.
  • the linker is cleaved at the drug's linker portion, the antitumor compound is released in its unmodified structure, thus exerting its original antitumor effect.
  • the antibody-drug conjugate "retains its biological activity" in the drug formulation.
  • antibody is used in the broadest sense to encompass various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, and antibody fragments (or antigen-binding fragments, or antigen-binding portions), as long as they exhibit the desired antigen-binding activity.
  • Antibodies can refer to immunoglobulins, which are tetrapeptide chains composed of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. The amino acid composition and sequence of the constant region of the immunoglobulin heavy chain differ, thus their antigenicity also differs.
  • immunoglobulins can be divided into five classes, or isotypes of immunoglobulins: IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ chains, respectively.
  • IgM immunoglobulins
  • IgD immunoglobulins
  • IgG immunoglobulins
  • IgA immunoglobulins
  • IgE immunoglobulins
  • different subclasses can be distinguished; for example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • Light chains are classified into ⁇ chains or ⁇ chains based on differences in their constant regions.
  • Each of the five classes of Ig can have either a ⁇ chain or a ⁇ chain.
  • variable region The sequence of approximately 110 amino acids near the N-terminus of the antibody heavy and light chains varies considerably, forming the variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable, forming the constant region (C region).
  • the variable region includes three hypervariable regions (CDRs) and four relatively conserved backbone regions (FRs). The three hypervariable regions determine the antibody's specificity and are also known as complementarity-determining regions (CDRs).
  • Each light chain variable region (VL) and heavy chain variable region (VH) consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the three CDRs of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDRs of the heavy chain refer to HCDR1, HCDR2, and HCDR3.
  • CDR contact ligand
  • the amino acid sequence boundaries of CDRs can be determined using various well-known schemes, such as the "Kabat” numbering rule (see Kabat et al. (1991), “Sequences of Proteins of Immunological Interest", 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD), the "Chothia” numbering rule, the “ABM” numbering rule, the "contact” numbering rule (see Martin, ACR. Protein Sequence and Structure Analysis of Antibody Variable Domains[J]. 2001), and the ImMunoGenTics (IMGT) numbering rule (Lefranc, M.P. et al., Dev. Comp. Immunol., 27, 55-77 (2003); Front Immunol. 2018 Oct 16; 9:2278), etc.
  • IMGT ImMunoGenTics
  • antigen-binding fragment or “functional fragment” or “antigen-binding portion” refer to one or more fragments of an intact antibody that retain the ability to specifically bind to an antigen. It has been shown that fragments of full-length antibodies can be used for antigen-binding function.
  • binding fragments encompassed in the term “antigen-binding fragment” include: (i) a Fab fragment, a monovalent fragment consisting of VL, VH, CL, and CH1 domains; (ii) an F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments connected by disulfide bridges on their hinge regions; (iii) an Fd fragment consisting of VH and CH1 domains; (iv) an Fv fragment consisting of the VH and VL domains of a single arm of the antibody; (v) dsFv, a stable antigen-binding fragment formed by interchain disulfide bonds between VH and VL; (vi) scFv; and (vii) bispecific, bispecific, and multispecific antibodies comprising fragments such as scFv, dsFv, and Fab.
  • binding refers to the binding of an antibody to an epitope on a pre-defined antigen.
  • antibodies bind with an affinity (KD) of approximately less than 10 ⁇ 8 M, such as approximately less than 10 ⁇ 9 M, 10 ⁇ 10 M, 10 ⁇ 11 M, or even smaller.
  • KD refers to the dissociation equilibrium constant of a specific antibody-antigen interaction.
  • the antibodies of this disclosure bind IL-5 with a dissociation equilibrium constant (KD) of less than about 10 ⁇ 7 M, such as less than about 10 ⁇ 8 M, 10 ⁇ 9 M, or 10 ⁇ 10 M or smaller, for example, as determined in a BIACORE instrument using surface plasmon resonance (SPR) technology.
  • SPR surface plasmon resonance
  • Homology refers to the sequence similarity between two polynucleotide sequences or two polypeptides. Two compared sequences are homologous at positions occupied by the same bases or amino acid monomer subunits; for example, if every position in two DNA molecules is occupied by adenine. The percentage of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared multiplied by 100. For example, in optimal sequence alignment, if 6 out of 10 positions in two sequences match or are homologous, then the two sequences are 60% homologous; if 95 out of 100 positions in two sequences match or are homologous, then the two sequences are 95% homologous.
  • comparisons are made when aligning two sequences to give the maximum percentage of homology.
  • comparisons can be performed using the BLAST algorithm, where the algorithm's parameters are chosen to give the maximum match between the sequences over the entire length of each reference sequence.
  • the following references relate to the BLAST algorithm, which is frequently used in sequence analysis: BLAST Algorithms: Altschul, S.F. et al., (1990) J. Mol. Biol. 215: 403-410; Gish, W. et al., (1993) Nature Genet. 3: 266-272; Madden, T.L. et al., (1996) Meth. Enzymol. 266: 131-141; Altschul, S.F. et al.
  • “giving” and “treatment” refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid.
  • “Giving” and “treatment” can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods.
  • Cellular treatment includes contact between a reagent and cells, as well as contact between a reagent and a fluid, wherein the fluid is in contact with the cells.
  • “Giving” and “treatment” also mean the treatment of, for example, cells, by means of a reagent, diagnostic agent, conjugate composition, or by means of another cell in vitro and ex vivo.
  • “treatment” refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic applications.
  • Treatment means administering an oral or topical therapeutic agent, such as a composition comprising any of the compounds disclosed herein, to a patient who has symptoms of one or more diseases, and the therapeutic agent is known to have a therapeutic effect on these symptoms.
  • a therapeutic agent is administered in a treated patient or population in an amount that effectively relieves symptoms of one or more diseases to induce the regression of such symptoms or inhibit their progression to any clinically measurable extent.
  • the amount of a therapeutic agent that effectively relieves any specific disease symptom can vary depending on a variety of factors, such as the patient's disease state, age, and weight, and the drug's ability to produce the desired therapeutic effect in the patient.
  • Whether the disease symptoms have been relieved can be evaluated using any clinical testing methods commonly used by a physician or other healthcare professional to assess the severity or progression of the symptoms.
  • the embodiments of this disclosure e.g., treatment methods or products
  • may be ineffective in alleviating symptoms of each target disease they should reduce symptoms of the target disease in a statistically significant number of patients, as determined by any statistical test known in the art, such as the Student t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test.
  • an "effective amount” includes the amount sufficient to improve or prevent the symptoms or condition of a medically diagnosed disease.
  • An effective amount also means the amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects.
  • An effective amount can be the maximum dose or administration regimen that avoids significant side effects or toxicity.
  • subject and “patient” refer to mammals, especially primates, and particularly humans.
  • the term "combination" as used in this disclosure refers to a route of administration in which at least one dose of an anti-PD-L1 antibody and at least one dose of an anti-CTLA-4 antibody are administered within a specified time period, wherein both drugs exhibit pharmacological effects.
  • the time period can be within a dosing cycle, such as within 4 weeks, 3 weeks, 2 weeks, 1 week, or within 24 hours, or within 12 hours, etc.
  • the anti-PD-L1 antibody and anti-CTLA-4 antibody, along with other classes of drugs can be administered simultaneously or sequentially. This period includes treatment in which the anti-PD-L1 antibody and anti-CTLA-4 antibody are administered via the same or different routes of administration.
  • the route of administration for the combination described in this disclosure is selected from simultaneous administration, independently formulated and co-administered, or independently formulated and sequentially administered.
  • Example 1 An open-label, multicenter Phase Ib/II clinical trial of anti-CTLA-4 antibody combined with anti-PD-L1 antibody and anti-VEGF antibody for the treatment of hepatocellular carcinoma.
  • the anti-PD-L1 antibody has the heavy chain sequence shown in SEQ ID NO:9 and the light chain sequence shown in SEQ ID NO:10. Dosage form: injection, strength: 600mg/12mL.
  • Anti-CTLA-4 antibody the heavy chain sequence of which is shown in SEQ ID NO:19, and the light chain sequence of which is shown in SEQ ID NO:20.
  • Dosage form sterile injection, strength: 50 mg/10 mL.
  • An anti-VEGF antibody the heavy chain sequence of which is shown in SEQ ID NO:29, and the light chain sequence of which is shown in SEQ ID NO:30.
  • Phase 1 Dose exploration + dose confirmation phase: Patients with pathologically confirmed, incurable advanced HCC who have failed standard treatment or are unwilling to receive standard treatment;
  • Second stage (the efficacy extension stage): Patients with pathologically confirmed, incurable advanced HCC who have not received immunotherapy (including but not limited to: PD-1/L1 inhibitors, CTLA-4 inhibitors) and have received ⁇ 1 line of previous systemic therapy.
  • immunotherapy including but not limited to: PD-1/L1 inhibitors, CTLA-4 inhibitors
  • Phase 1 Dose Exploration + Dose Confirmation: This phase aims to enroll patients with advanced HCC who have failed standard treatment.
  • Anti-PD-L1 antibody will be administered in combination with anti-CTLA-4 antibody; the order of administration will be: anti-PD-L1 antibody first, followed by anti-CTLA-4 antibody.
  • Anti-PD-L1 antibody 20 mg/kg, once every 3 weeks (Q3W), intravenous injection (IV);
  • Anti-CTLA-4 antibody 1) 1 mg/kg, Q6W; or 2) 4 mg/kg, once a day.
  • Phase 2 ( Extended Efficacy Phase): This phase of the study included HCC patients who had not previously received immunotherapy (including but not limited to PD-1/L1 inhibitors and CTLA-4 inhibitors) and had received ⁇ 1 line of prior treatment.
  • Anti-PD-L1 antibody (20 mg/kg, Q3W) + anti-VEGF antibody (15 mg/kg, Q3W);
  • Anti-PD-L1 antibody (20 mg/kg, Q3W) + anti-VEGF antibody (15 mg/kg, Q3W) + anti-CTLA-4 antibody (1 mg/kg, Q6W);
  • Anti-PD-L1 antibody (20 mg/kg, Q3W) + anti-VEGF antibody (15 mg/kg, Q3W) + anti-CTLA-4 antibody (4 mg/kg, administered once at C1);
  • Anti-PD-L1 antibody (20 mg/kg, Q3W) + anti-VEGF antibody (15 mg/kg, Q3W) + anti-CTLA-4 antibody (4 mg/kg, administered once each at C1 and C5);
  • Each treatment cycle is 3 weeks.
  • C1 refers to the first treatment cycle and C5 refers to the fifth treatment cycle.
  • C1 to C4 correspond to the dosing period I, and C5 onwards corresponds to the dosing period II.
  • Table 4.1 shows the baseline characteristics of subjects receiving two- or three-drug combination therapy, and the efficacy evaluation results are shown in Table 4.2.
  • Table 4.2 the three-drug combination regimen of anti-CTLA-4 antibody, anti-PD-L1 antibody, and anti-VEGF antibody provided in this embodiment significantly improves the proportion of patients achieving complete remission (CR) and partial remission (PR) compared to the two-drug combination regimen of anti-PD-L1 antibody and anti-VEGF antibody, resulting in a significantly higher objective response rate in clinical cancer treatment and better clinical benefits for patients.
  • Example 2 A randomized, open-label, multicenter phase II clinical trial of anti-CTLA-4 antibody combined with anti-PD-L1 antibody and platinum-based chemotherapy as first-line treatment for advanced non-small cell lung cancer.
  • An anti-PD-L1 antibody the heavy chain sequence of which is shown in SEQ ID NO:9, and the light chain sequence of which is shown in SEQ ID NO:10.
  • Dosage form injection, strength: 600mg/12mL.
  • Anti-CTLA-4 antibody the heavy chain sequence of which is shown in SEQ ID NO:19, and the light chain sequence of which is shown in SEQ ID NO:20.
  • Dosage form sterile injection, strength: 50 mg/10 mL.
  • Pemetrexed disodium for injection specification: 0.2g (calculated as pemetrexed);
  • Paclitaxel for injection (albumin-bound), specification: 100mg/vial (calculated based on paclitaxel content);
  • Carboplatin for injection specification: 0.1g/vial;
  • Cisplatin injection specification: 6mL:30mg.
  • Dosage-assured stage Patients with relapsed or advanced NSCLC who have not received prior systemic treatment and whose PD-L1 TPS is confirmed by histology or cytology, and whose PD-L1 TPS is ⁇ 50% as confirmed by a central laboratory. Note: Patients who have previously received neoadjuvant or adjuvant chemotherapy/radiotherapy and whose relapse or metastasis has occurred more than 6 months after the end of treatment can be enrolled.
  • Phase 1 (Phase Ib) : Anti-PD-L1 antibody combined with anti-CTLA-4 antibody; administration order: first administer anti-PD-L1 antibody, then administer anti-CTLA-4 antibody.
  • Anti-PD-L1 antibody 20 mg/kg, once every 3 weeks (Q3W), intravenous injection (IV);
  • Anti-CTLA-4 antibody 1) 1 mg/kg, Q6W; or 2) 4 mg/kg, once a day.
  • Phase Two Phase II:
  • Anti-PD-L1 antibody (20 mg/kg, Q3W) + anti-CTLA-4 antibody (1 mg/kg, Q6W) + platinum-based chemotherapy based on tumor tissue subtype (non-squamous carcinoma: 4 cycles of pemetrexed + carboplatin/cisplatin combined administration, followed by pemetrexed monotherapy maintenance until the treatment end criteria are met; squamous carcinoma: 4 cycles of albumin-bound paclitaxel/paclitaxel + carboplatin/cisplatin combined administration);
  • Anti-PD-L1 antibody (20 mg/kg, Q3W) + anti-CTLA-4 antibody (4 mg/kg, C1 administration once) + platinum-based chemotherapy based on tumor tissue typing;
  • Anti-PD-L1 antibody (20 mg/kg, Q3W) + anti-CTLA-4 antibody (4 mg/kg, once administered at C1 and once administered at C5) + platinum-based chemotherapy based on tumor tissue typing;
  • Anti-PD-L1 antibody (1200mg, Q3W) + anti-CTLA-4 antibody (280mg, once administered at C1, 70mg every Q6W starting at C5) + platinum-based chemotherapy based on tumor tissue typing;
  • Anti-PD-L1 antibody (1200mg, Q3W) + platinum-based chemotherapy based on tumor tissue typing.
  • the randomization stratification factors were: 1) PD-L1 expression (PD-L1 ⁇ 1% vs. 1-49%); 2) histological type (non-squamous NSCLC vs. squamous cell carcinoma).
  • non-squamous NSCLC pemetrexed 500 mg/ m2 + carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/ m2 were administered for 4 cycles, followed by pemetrexed maintenance.
  • albumin-bound paclitaxel 100 g/ m2 was administered on days 1, 8, and 15, or paclitaxel 175 mg/ m2 + carboplatin/cisplatin were administered for 4 cycles.
  • Table 5.1 shows the baseline characteristics of subjects receiving the triple-drug combination therapy, and the efficacy evaluation results are shown in Table 5.2 and Figure 1.
  • the anti-CTLA-4 antibody combined with anti-PD-L1 antibody and chemotherapy regimen provided in this embodiment has a better proportion of patients achieving complete remission (CR) and partial remission (PR), significantly improving the objective response rate in clinical cancer treatment, and patients can obtain better clinical benefits.
  • CR complete remission
  • PR partial remission
  • Example 3 A randomized, open-label, multicenter phase II clinical trial of anti-CTLA-4 antibody combined with anti-PD-L1 antibody and platinum-based chemotherapy as first-line treatment for advanced biliary tract cancer.
  • Anti-CTLA-4 antibody Its heavy chain sequence is SEQ ID NO: 9, and its light chain sequence is SEQ ID NO: 10. Specification: 50mg/10mL.
  • Anti-PD-L1 antibody Its heavy chain sequence is SEQ ID NO: 23, and its light chain sequence is SEQ ID NO: 24. Specification: 12mL:0.6g.
  • Age 18 to 75 years old (inclusive, calculated from the date of signing informed consent), both men and women are eligible;
  • Anti-PD-L1 antibody 1200 mg, intravenous infusion; once a day on day 1 of each cycle, with each cycle lasting 3 weeks (Q3W).
  • Anti-CTLA-4 antibody 280 mg once on day 1 of the first treatment cycle (each treatment cycle is 3 weeks); starting from the fifth treatment cycle, 70 mg once on day 1 every 2 cycles (i.e., 70 mg Q6W). Intravenous infusion.
  • Gemcitabine injection 1000 mg/ m2 , intravenous infusion; administered once on days 1 and 8 of each cycle, with each cycle lasting 3 weeks (Q3W); continued until tumor progression, intolerable toxicity, or other criteria for termination of treatment.
  • Cisplatin injection 25 mg/ m2 , intravenous infusion (requires hydration), slow infusion; administered once on days 1 and 8 of each cycle, with each cycle consisting of 3 weeks (Q3W); a maximum of 8 cycles.
  • Cohort A Receiving anti-PD-L1 antibody + anti-CTLA-4 antibody + gemcitabine + cisplatin treatment
  • Cohort B Receiving anti-PD-L1 antibody + gemcitabine + cisplatin treatment
  • Dosing order According to the study protocol, for drugs to be administered on the same day, the order should be: first administer anti-PD-L1 antibody, then anti-CTLA-4 antibody, and finally platinum-based chemotherapy. Dosing should be completed on the same day whenever possible.
  • body weight should be measured before each D1 cycle. If the weight change compared to C1D1 is ⁇ 10% (increase or decrease), the investigator will determine whether to recalculate the dosage. If the weight change compared to C1D1 is ⁇ 10% (increase or decrease), the dosage needs to be recalculated. The weight used for each D8 cycle is recommended to be based on the weight measured during D1. After recalculating the dosage, subsequent weight changes should be compared to the weight used in the most recent dosage recalculation. For ease of administration, an error of ⁇ 5% between the actual dosage and the planned dosage is acceptable.
  • Table 6 shows the efficacy evaluation results for the patients.
  • a total of 80 patients with advanced BTC were enrolled (ITT set), with 40 patients randomly assigned to each of the two groups.
  • the objective response rate (ORR) of patients receiving anti-PD-L1 antibody + anti-CTLA-4 antibody + gemcitabine + cisplatin (cohort A) was significantly higher than that of cohort B.
  • the median progression-free survival for cohort A and cohort B was 6.8 months and 5.5 months, respectively, with a HR of 0.72 (0.35-1.48). Patients experienced significant clinical benefit and good tolerability.
  • Example 4 A randomized, open-label, parallel-controlled, multicenter phase II/III study of anti-CTLA-4 antibody combined with anti-PD-L1 antibody and platinum-based doublet chemotherapy as first-line treatment for STK11/KEAP1/KRAS-mutant advanced or metastatic non-squamous non-small cell lung cancer.
  • An anti-PD-L1 antibody the heavy chain sequence of which is shown in SEQ ID NO:9, and the light chain sequence of which is shown in SEQ ID NO:10.
  • Dosage form injection, strength: 600mg/12mL.
  • Anti-CTLA-4 antibody the heavy chain sequence of which is shown in SEQ ID NO:19, and the light chain sequence of which is shown in SEQ ID NO:20.
  • Dosage form sterile injection, strength: 50 mg/10 mL.
  • Pemetrexed disodium for injection specification: 0.2g (calculated as pemetrexed);
  • Carboplatin for injection specification: 0.1g/vial.
  • Advanced stage is defined as stage IIIB according to the International Association for the Study of Lung Cancer (8th edition) TNM staging system, and who are no longer suitable for radical surgery or radiotherapy.
  • Phase 1 The primary objective was to evaluate the efficacy and safety of anti-PD-L1 antibody combined with anti-CTLA-4 antibody and platinum-based doublet chemotherapy in patients with STK11/KEAP1/KRAS mutations or co-mutations in advanced or metastatic non-squamous non-small cell lung cancer.
  • Anti-PD-L1 antibody + anti-CTLA-4 antibody + platinum-based doublet chemotherapy among which:
  • Pemetrexed, 500 mg/m2, intravenous infusion, every 3 weeks is one dosing cycle, administered on day 1 of each cycle.
  • Carboplatin, AUC 5 mg/mL/min, intravenous infusion, every 3 weeks is one dosing cycle, administered on day 1 of each cycle, for 4-6 cycles.
  • Arm D Anti-PD-L1 antibody + anti-CTLA-4 antibody + platinum-based doublet chemotherapy; among which:
  • Anti-CTLA-4 antibody 280 mg in C1, 70 mg every 6 weeks starting from C5, administered by intravenous infusion;
  • Pemetrexed, 500 mg/m2, intravenous infusion, every 3 weeks is one dosing cycle, administered on day 1 of each cycle;
  • Carboplatin, AUC 5 mg/mL/min, intravenous infusion, every 3 weeks is one dosing cycle, administered on day 1 of each cycle, for 4-6 cycles.
  • Phase II The primary objective is to evaluate the efficacy and safety of anti-PD-L1 antibody combined with anti-CTLA-4 antibody and platinum-based doublet chemotherapy as first-line treatment. Patients will receive anti-PD-L1 antibody combined with anti-CTLA-4 antibody and platinum-based doublet chemotherapy.
  • ORR objective response rate
  • DoR investigator-assessed duration of response
  • DCR investigator-assessed disease control rate
  • PFS investigator-assessed progression-free survival
  • OS overall survival
  • Example 5 A randomized, open-label, parallel-controlled, multicenter phase III study of anti-CTLA-4 antibody combined with anti-PD-L1 antibody and platinum-based doublet chemotherapy as first-line treatment for hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • An anti-PD-L1 antibody the heavy chain sequence of which is shown in SEQ ID NO:9, and the light chain sequence of which is shown in SEQ ID NO:10.
  • Dosage form injection, strength: 600mg/12mL.
  • Anti-CTLA-4 antibody the heavy chain sequence of which is shown in SEQ ID NO:19, and the light chain sequence of which is shown in SEQ ID NO:20.
  • Dosage form sterile injection, strength: 50 mg/10 mL.
  • Pemetrexed disodium for injection specification: 0.2g (calculated as pemetrexed);
  • Carboplatin for injection specification: 0.1g/vial.
  • measurable lesion There must be at least one measurable lesion that meets RECISTv1.1 (Appendix 2, according to RECISTv1.1, the measurable lesion must have a long diameter ⁇ 10mm on spiral CT scan or a short diameter ⁇ 15mm on enlarged lymph node); lesions that have undergone local treatment may be selected as target lesions if there is clear evidence that they have significantly progressed since the end of treatment.
  • Anti-CTLA-4 antibody 280 mg for C1D1, 70 mg every 6 weeks starting from C5D1, intravenously;
  • Anti-PD-L1 antibody 1200 mg, intravenous infusion, Q3W;
  • Anti-VEGF antibody 15 mg/kg, intravenous infusion, Q3W, with each 3-week period constituting one treatment cycle.

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Abstract

本发明提供抗PD-L1抗体联合抗CTLA-4抗体治疗肿瘤的方法，以及抗PD-L1抗体和抗CTLA-4抗体联合在制备治疗肿瘤的药物中的用途。

Description

抗PD-L1抗体和抗CTLA-4抗体联合治疗肿瘤
本公开要求如下专利申请的优先权：于2024.7.19提交，申请号为2024109726031的中国专利申请；于2024.6.13提交，申请号为2024107609067的中国专利申请；于2025.5.15提交，申请号为2025106251088的中国专利申请；前述专利申请的全部内容通过引用结合至本公开中。
技术领域
本公开属于医药领域，涉及抗PD-L1抗体和抗CTLA-4抗体联合治疗肿瘤的方法及医药用途。
背景技术
人细胞毒性T淋巴细胞相关抗原4(CTLA-4)基因定位于2号染色体长臂3区3带(2q33)，主要表达于活化的T淋巴细胞表面，与T细胞表面的协同刺激分子受体(CD28)在基因结构、染色体定位、序列的同源性及基因表达具有十分相近的关系，可与抗原递呈细胞(APC)表面的协同刺激分子(B7)结合。但不同于CD28，CTLA-4与B7分子结合后是抑制T细胞活化。其作用机制尚未完全阐明，可能是通过其胞外域起竞争配体作用，通过占据APC的B7配体，从而阻止CD28信号，或通过其胞内域介导一负性信号而抑制T细胞活化。外源性抗原及肿瘤特异性相关靶抗原刺激引发机体抗肿瘤免疫。初始阶段由于CTLA-4水平有限而使B7与CD28作用占优势，T细胞被激活分泌IL-2等细胞因子，并扩增、分化成效应T细胞。而随着激活T细胞的CTLA-4表达量上升，在免疫反应的后期CTLA-4与CD28竞争性地与B7分子结合，抑制T细胞从G期进入S期及IL-2转录因子的活性，从而下调或终止T细胞反应。因此，CTLA-4被认为是抑制机体抗肿瘤的免疫因子，开发抗CTLA-4抗体用于肿瘤的更为安全、有效的免疫治疗方案，是目前肿瘤靶向免疫治疗领域需要解决的重要问题。
发明内容
本公开提供抗PD-L1抗体药物联合抗CTLA-4抗体治疗肿瘤的方法及医药用途。
在一些实施方案中，本公开提供如下任一项所示的用途：
(1)抗PD-L1抗体联合抗CTLA-4抗体在制备治疗肿瘤的药物中的用途；
(2)抗PD-L1抗体和抗CTLA-4抗体的组合在制备治疗肿瘤的药物中的用途；
(3)抗PD-L1抗体用于治疗肿瘤，其中，所述抗PD-L1抗体联合抗CTLA-4抗体施用于受试者；
(4)抗CTLA-4抗体用于治疗肿瘤，其中，所述抗CTLA-4抗体联合抗PD-L1抗体施用于受试者；
(5)抗PD-L1抗体用于治疗患有肿瘤的受试者，其中，所述受试者还施用抗CTLA-4抗体；
(6)抗CTLA-4抗体用于治疗患有肿瘤的受试者，其中，所述受试者还施用抗PD-L1抗体。
在一些实施方案中，本公开提供治疗肿瘤的方法，包括向有需要的受试者施用治疗有效量的抗PD-L1抗体和抗CTLA-4抗体。
在一些实施方案中，前述任一方法或用途，其进一步联合化疗剂、具有抗肿瘤活性的抗体、抗体药物偶联物、和/或抗血管生成剂。
在一些实施方案中，本公开提供如下任一项所示的用途：
(1)抗PD-L1抗体联合抗CTLA-4抗体和抗血管生成剂在制备治疗肿瘤的药物中的用途；
(2)抗PD-L1抗体、抗CTLA-4抗体和抗血管生成剂的组合在制备治疗肿瘤的药物中的用途；
(3)抗PD-L1抗体用于治疗肿瘤，其中，所述抗PD-L1抗体联合抗CTLA-4抗体和抗血管生成剂施用于受试者；
(4)抗CTLA-4抗体用于治疗肿瘤，其中，所述抗CTLA-4抗体联合抗PD-L1抗体和抗血管生成剂施用于受试者；
(5)抗PD-L1抗体用于治疗患有肿瘤的受试者，其中，所述受试者还施用抗CTLA-4抗体和抗血管生成剂；
(6)抗CTLA-4抗体用于治疗患有肿瘤的受试者，其中，所述受试者还施用抗PD-L1抗体和抗血管生成剂。
在一些实施方案中，本公开提供治疗肿瘤的方法，包括向有需要的受试者施用治疗有效量的抗PD-L1抗体、抗CTLA-4抗体和抗血管生成剂。
在一些实施方案中，本公开提供如下任一项所示的用途：
(1)抗PD-L1抗体联合抗CTLA-4抗体和化疗剂在制备治疗肿瘤的药物中的用途；
(2)抗PD-L1抗体、抗CTLA-4抗体和化疗剂的组合在制备治疗肿瘤的药物中的用途；
(3)抗PD-L1抗体用于治疗肿瘤，其中，所述抗PD-L1抗体联合抗CTLA-4抗体和化疗剂施用于受试者；
(4)抗CTLA-4抗体用于治疗肿瘤，其中，所述抗CTLA-4抗体联合抗PD-L1抗体和化疗剂施用于受试者；
(5)抗PD-L1抗体用于治疗患有肿瘤的受试者，其中，所述受试者还施用抗CTLA-4抗体和化疗剂；
(6)抗CTLA-4抗体用于治疗患有肿瘤的受试者，其中，所述受试者还施用抗PD-L1抗体和化疗剂。
在一些实施方案中，本公开提供治疗肿瘤的方法，包括向有需要的受试者施用治疗有效量的抗PD-L1抗体、抗CTLA-4抗体和化疗剂。
在一些实施方案中，前述任一方法或用途，其中所述抗CTLA-4抗体联合抗PD-L1，且不与抗NECTIC-4抗体药物偶联物联用。其中，抗Nectin-4抗体药物偶联物来源于WO2022228406A、WO2023221971A中的任意结构的抗体药物偶联物。
在一些实施方案中，所述肿瘤是实体瘤。一些实施方案中，所述肿瘤是恶性实体瘤。
在本公开，“恶性(malignant)实体瘤”是指具有致癌性的肿瘤。具有致癌性的肿瘤可以侵入到身体内周围的组织中，且随着这些肿瘤的生长，有些癌细胞或许还会游离到身体的其它部位，以形成其它的“继发性”肿瘤(“secondary”tumors)，也称为转移(瘤)(metastases)。
在一些实施例方案中，肿瘤为晚期、复发或转移性实体瘤。在一些实施方案中，肿瘤是经标准治疗失败的实体瘤。在一些实施例方案中，肿瘤是未经标准治疗的实体瘤。一些实施方案中，所述肿瘤患者接受系统性抗肿瘤治疗。一些实施方案中，所述肿瘤患者未接受系统性抗肿瘤治疗。
在本公开，系统性抗肿瘤治疗方案是本领域技术人员所熟知的，例如，经过监管部门批准的治疗指南中所披露的治疗方案。例如包括但不限于NCCN指南、CSCO指南中提供的关于各种癌症的标准治疗方案的详细最新信息。
在一些实施方案中，肿瘤选自肝癌、肺癌(例如，小细胞肺癌或非小细胞肺癌)、胆道癌。
在一些实施方案中，肿瘤为肝癌。在一些具体的实施方案中，肝癌为不可切除的局部晚期或转移性肝癌。在一些具体的实施方案中，肝癌为BCLC分期(巴萨罗那临床肝癌分期)为B期或C期。
在一些实施方案中，肿瘤为非小细胞肺癌。在一些具体的实施方案中，为经组织或细胞学确诊的复发或晚期NSCLC。在一些具体的实施方案中，为PD-L1 TPS＜50％的非小细胞肺癌。
在一些实施方案中，肿瘤选自鳞状或非鳞状NSCLC。
在一些实施方案中，为经组织学或细胞学确诊的晚期或转移性非鳞状NSCLC受试者。晚期定义：按照国际肺癌研究协会(第8版TNM分期标准判断分期为ⅢB期期，且已不适合开展根治性手术或放疗治疗)。
在一些实施方案中，为驱动基因阳性非小细胞肺癌。在一些具体的实施方案中，所述驱动基因阳性的非小细胞肺癌为STK11、KEAP1、KRAS突变或共突变的非小细胞肺癌。
在一些实施方案中，所述肿瘤为胆道腺癌，在一些实施方案中，所述肿瘤为胆囊癌、肝内胆管癌、肝外胆管癌；在一些实施方案中，所述肿瘤为局部晚期或复发/转移性胆囊癌、肝内胆管癌、肝外胆管癌。
在一些实施方案中，所述肿瘤为经组织学或细胞学确诊的不可手术切除的局部晚期、或复发/转移性胆囊癌、肝内胆管癌、肝外胆管癌。
<抗PD-L1抗体>
在一些实施方案中，所述抗PD-L1抗体包含重链可变区(VH)和轻链可变区(VL)，其中所述重链可变区包含如SEQ ID NO:1-3所示的HCDR1、HCDR2和HCDR3，所述轻链可变区包含如SEQ ID NO:4-6所示的LCDR1、LCDR2和LCDR3。
其中，前面所述的各CDR序列如下表1所示：
表1.抗PD-L1抗体的CDR序列(Kabat方案)
在一些实施方案中，抗PD-L1抗体包含前述HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3中任意1个，或任意2、3、4、5或6个的组合。
在一些实施方案中，抗PD-L1抗体包含重链可变区(VH)和轻链可变区(VL)：其中，所述VH包含SEQ ID NO:7所示氨基酸序列中的HCDR1、HCDR2和HCDR3，所述VL包含如SEQ ID NO:8所示氨基酸序列中的LCDR1、LCDR2和LCDR3。上述的CDR是根据Kabat、IMGT、Chothia、AbM或Contact定义方案定义的。在一些具体的实施方案中，所述CDR是根据Kabat定义方案定义的。
在一些实施方案中，抗PD-L1抗体为嵌合、人源化、全人抗体或其抗原结合片段。
在一些实施方案中，抗PD-L1抗体包含重链可变区(VH)和轻链可变区(VL)，其中，所述VH包含如SEQ ID NO:7所示或与之具有至少80％、90％同一性的氨基酸序列，和，所述VL包含如SEQ ID NO:8所示或与之具有至少80％、90％同一性的氨基酸序列。
重链可变区：
轻链可变区：
注：下划线部分为依照Kabat编号规则确定的CDR区。
在一些实施方案中，抗PD-L1抗体包含前述VH、VL中的任意一个或两个。
在一些实施方案中，抗PD-L1抗体进一步包含重链恒定区和/或轻链恒定区。其中，抗体的重链恒定区可选自人IgG1、IgG2、IgG3、IgG4及其变体的恒定区。在一些实施方案中，轻链恒定区可选自人源κ、λ链或其变体的轻链恒定区。
在一些实施方案中，抗PD-L1抗体包含重链和轻链，所述重链包含如SEQ ID NO:9所示或与之具有至少80％、至少90％序列同一性的氨基酸序列；和/或，所述轻链包含如SEQ ID NO:10所示或与之具有至少80％、至少90％同一性的氨基酸序列。
在一些实施方案中，抗PD-L1抗体包含如SEQ ID NO:9所示氨基酸序列的重链，和如SEQ ID NO:10所示氨基酸序列的轻链。
抗PD-L1抗体的重链序列：
SEQ ID NO:9；
抗PD-L1抗体的轻链序列：
SEQ ID NO:10；
注：划线部分为抗体重链或轻链的可变区序列，未划线部分为抗体恒定区序列。
在一些实施方案中，上述抗PD-L1抗体或其抗原结合片段的制备可以参考WO2017084495A1、WO2018210230A1，本公开通过引用将WO2017084495A1、WO2018210230A1中抗体序列、制备方法、组合物的相关内容结合至本公开。
在本公开的上下文中，“至少80％、90％”涵盖80％及以上，例如至少80％、至少81％、至少82％、至少83％、至少84％、至少85％、至少86％、至少87％、至少88％、至少89％、至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％，以及任意两者之间的数值范围。
在一些实施方案中，抗PD-L1抗体的给药剂量为50mg-5000mg，例如100mg-5000mg，100mg-4500mg，100mg-4000mg，100mg-3500mg，100mg-3000mg，100mg-2500mg，100mg-2000mg，100mg-1500mg，500mg-3500mg，500mg-3000mg，500mg-2500mg，500mg-2000mg，500mg-1500mg，800mg-3500mg，800mg-3000mg，800mg-2500mg，800mg-2000mg，800mg-1500mg，或1000mg-1500mg，800mg-1800mg，或1000mg-1800mg；以及任意两者之间的数值范围。
在一些实施方案中，抗PD-L1抗体的给药剂量为约50mg、约60mg、约70mg、约75mg、约100mg、约125mg、约150mg、约175mg、约200mg、225mg、约250mg、约375mg、约400mg、约425mg、约450mg、约475mg、约500mg、约550mg、约600mg、650mg、约700mg、约750mg、约800mg、约850mg、约900mg、约950mg、约1000mg、约1050mg、约1100mg、约1150mg、约1200mg、约1250mg、约1300mg、约1350mg、约1400mg、约1450mg、约1500mg、1550mg、约1600mg、约1650mg、约1700mg、约1750mg、约1800mg、约1850mg、约1900mg、约1950mg、2000mg、约2050mg、约2100mg、约2150mg、约2200mg、约2250mg、约2300mg、约2350mg、约2400mg、2450mg、约2500mg、约2550mg、约2600mg、约2650mg、约2700mg、约2750mg、约2800mg、约2850mg、2900mg、约2950mg、约3000mg、约3050mg、约3100mg、约3150mg、约3200mg、约3250mg、约3300mg、约3350mg、约3400mg、3450mg、约3500mg、约3550mg、约3600mg、约3650mg、约3700mg、约3750mg、约3800mg、约3850mg、3900mg、约3950mg、约4000mg、约4500mg、约4800mg。
在一些实施方案中，抗PD-L1抗体的给药剂量为约1200mg或约1800mg。
在一些实施方案中，所述抗PD-L1抗体的给药剂量为1mg/kg-500mg/kg，1mg/kg-50mg/kg，5mg/kg-50mg/kg，10mg/kg-50mg/kg，15mg/kg-50mg/kg，20mg/kg-50mg/kg，1mg/kg-30mg/kg，5mg/kg-30mg/kg，10mg/kg-30mg/kg，或15mg/kg-30mg/kg；或者为这些点值之间的任意范围。
在一些实施方案中，所述抗PD-L1抗体的给药剂量为约5mg/kg、约6mg/kg、约7mg/kg、约8mg/kg、约9mg/kg、约10mg/kg、约11mg/kg、约12mg/kg、约13mg/kg、约14mg/kg、约15mg/kg、约16mg/kg、约17mg/kg、约18mg/kg、约19mg/kg、约20mg/kg、约21mg/kg、约22mg/kg、约23mg/kg、约24mg/kg、约25mg/kg、约26mg/kg、约27mg/kg、约28mg/kg、约29mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约55mg/kg、约60mg/kg、约65mg/kg、约70mg/kg、约75mg/kg、约80mg/kg、约85mg/kg、约90mg/kg、约95mg/kg、约110mg/kg、约120mg/kg、约130mg/kg、约140mg/kg、约150mg/kg、约200mg/kg、约220mg/kg、约250mg/kg、约300mg/kg。或者为这些点值之间的任意数值范围。
在一些实施方案中，所述抗PD-L1抗体的给药剂量为约20mg/kg。
在一些实施方案中，所述抗PD-L1抗体的给药频率为每2周1次，每3周1次，每4周1次，或每6周1次。在一些具体的实施方案中，所述抗PD-L1抗体的给药频率为3周1次或4周1次。
在一些实施方案中，所述抗PD-L1抗体的给药方式为静脉注射给药。
<抗CTLA-4抗体>
在一些实施方案中，所述抗CTLA-4抗体包含重链可变区(VH)和轻链可变区(VL)，其中所述重链可变区包含如SEQ ID NO:11-13所示的HCDR1、HCDR2和HCDR3，所述轻链可变区包含如SEQ ID NO:14-16所示的LCDR1、LCDR2和LCDR3。
其中，前面所述的各CDR序列如下表2所示：
表2.抗CTLA-4抗体的CDR序列(Kabat方案)
在一些实施方案中，抗CTLA-4抗体包含前述HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3中任意1个，或任意2、3、4、5或6个的组合。
在一些实施方案中，抗CTLA-4抗体包含重链可变区(VH)和轻链可变区(VL)：其中，所述VH包含SEQ ID NO:17所示氨基酸序列中的HCDR1、HCDR2和HCDR3，所述VL包含如SEQ ID NO:18所示氨基酸序列中的LCDR1、LCDR2和LCDR3。上述的CDR是根据Kabat、IMGT、Chothia、AbM或Contact定义方案定义的。在一些具体的实施方案中，所述CDR是根据Kabat定义方案定义的。
在一些实施方案中，抗CTLA-4抗体为嵌合、人源化、全人抗体或其抗原结合片段。
在一些实施方案中，抗CTLA-4抗体包含重链可变区(VH)和轻链可变区(VL)，其中，所述VH包含如SEQ ID NO:17所示或与之具有至少80％、90％同一性的氨基酸序列，和，所述VL包含如SEQ ID NO:18所示或与之具有至少80％、90％同一性的氨基酸序列。
重链可变区：
轻链可变区：
在一些实施方案中，抗CTLA-4抗体包含前述VH、VL中的任意一个或两个。
在一些实施方案中，抗CTLA-4抗体进一步包含重链恒定区和/或轻链恒定区。其中，抗体的重链恒定区可选自人IgG1、IgG2、IgG3、IgG4及其变体的恒定区。在一些实施方案中，轻链恒定区可选自人源κ、λ链或其变体的轻链恒定区。
在一些实施方案中，抗CTLA-4抗体包含重链和轻链，所述重链包含如SEQ ID NO:19所示或与之具有至少80％、至少90％序列同一性的氨基酸序列；和/或，所述轻链包含如SEQ ID NO:20所示或与之具有至少80％、至少90％同一性的氨基酸序列。
在一些实施方案中，抗CTLA-4抗体包含如SEQ ID NO:19所示氨基酸序列的重链，和如SEQ ID NO:20所示氨基酸序列的轻链。
抗CTLA-4抗体的重链序列：
抗CTLA-4抗体的轻链序列：
注：划线部分为抗体重链或轻链的可变区序列，未划线部分为抗体恒定区序列。
在一些实施方案中，所述抗CTLA-4抗体的给药剂量为0.1-50mg/kg，例如0.5-50mg/kg、0.1-20mg/kg、0.5-10mg/kg、0.5-8mg/kg、0.5-6mg/kg、0.5-5mg/kg、1-50mg/kg、1-20mg/kg、1-10mg/kg、1-3.5mg/kg、1-4mg/kg、0.5-3.5mg/kg、3.5-10mg/kg、3.5-8mg/kg、3.5-6mg/kg、4-6mg/kg；或者为这些点值之间的任意范围。
在一些实施方案中，所述抗CTLA-4抗体的给药剂量为约0.1mg/kg，约0.2mg/kg，约0.3mg/kg，约0.4mg/kg，约0.5mg/kg，约0.6mg/kg，约0.7mg/kg，约0.8mg/kg，0.9mg/kg，约1.0mg/kg，约1.1mg/kg，约1.2mg/kg，约1.3mg/kg，约1.4mg/kg，约1.5mg/kg，约2.0mg/kg，约2.5mg/kg，约3.0mg/kg，约3.5mg/kg，约4.0mg/kg，约5.0mg/kg，约6.0mg/kg，约7.0mg/kg，约8.0mg/kg，约9.0mg/kg，约10.0mg/kg、约11mg/kg、约12mg/kg、约13mg/kg、约14mg/kg、约15mg/kg、约16mg/kg、约17mg/kg、约18mg/kg、约19mg/kg、约20mg/kg、约21mg/kg、约22mg/kg、约23mg/kg、约24mg/kg、约25mg/kg、约26mg/kg、约27mg/kg、约28mg/kg、约29mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg。或者为这些点值之间的任意数值范围。在一些具体的实施方案中，所述抗CTLA-4抗体的给药剂量为约1.0mg/kg，或约4.0mg/kg。
在一些实施方案中，所述抗CTLA-4抗体的给药剂量为5-1000mg，例如5-800mg，5-600mg，5-550mg，5-500mg，5-450mg，5-400mg，5-350mg，5-300mg，10-200mg，10-300mg，10-350mg，10-400mg，10-500mg，10-600mg，10-800mg，30-200mg，30-220mg，30-250mg，30-280mg，30-300mg，30-400mg，30-500mg，30-600mg，30-800mg，50-800mg，50-600mg，50-550mg，50-500mg，50-450mg，50-400mg，50-350mg，50-300mg，100-800mg，100-600mg，100-550mg，100-1000mg，100-450mg，100-400mg，100-350mg，100-300mg，150-300mg，150-400mg，200-300mg，200-400mg。或者为这些点值之间的任意数值范围。
在一些实施方案中，所述抗CTLA-4抗体的给药剂量为约5mg，约10mg，约20mg，约30mg，约40mg，约50mg，约60mg，约70mg，约80mg，约90mg，约100mg，约110mg，约120mg，约130mg，约140mg，约150mg，约160mg，约170mg，约180mg，约190mg，约200mg，约210mg，约220mg，约225mg，约230mg，约235mg，约240mg，约245mg，约250mg，约255mg，约260mg，约265mg，约270mg，约275mg，约280mg，约285mg，约290mg，约295mg，约300mg，约305mg，约310mg，约315mg，约320mg，约330mg，约340mg，约350mg，约360mg，约380mg，约400mg，约500mg，约600mg，约800mg。或者为这些点值之间的任意数值范围。在一些具体的实施方案中，所述抗CTLA-4抗体的给药剂量为约70mg或约280mg。
在一些实施方案中，所述抗CTLA-4抗体的给药频次为单次或多次给药。在一些实施方案中，所述抗CTLA-4抗体给药一次或两次。在一些实施方案中，所述抗CTLA-4抗体的给药频次为3周1次、4周1次、6周1次、8周1次、10周1次、12周1次、14周1次、或16周1次。
在一些实施方案中，所述抗CTLA-4抗体的给药方案为：
(1)给药剂量为3.5-10mg/kg，给药一次或两次；或，
(2)给药剂量为220-360mg给药一次或两次；或，
(3)给药剂量为0.5-3.5mg/kg，每3周1次、每6周1次或每9周1次给药；或，
(4)给药剂量为30-220mg，每3周1次、每6周1次或每9周1次给药。
在一些实施方案中，所述抗CTLA-4抗体的给药方案为：
(1)给药剂量为约3.5mg/kg、约4mg/kg、约4.5mg/kg、约5mg/kg、约5.5mg/kg或约6mg/kg，给药一次或两次；
(2)给药剂量为约220mg，约240mg，约260mg，约280mg，约300mg，约320mg，约340mg，或约360mg，给药一次或两次；
(3)给药剂量为约1.0mg/kg，约1.5mg/kg，约2mg/kg，约2.5mg/kg，约3.0mg/kg或约3.5mg/kg；每3周1次、每6周1次或每9周1次给药；
(4)给药剂量为约30mg，约40mg，约50mg，约60mg，约70mg，约80mg，约90mg，约100mg，约120mg，约150mg，约170mg，约190mg，或约200mg；每3周1次、每6周1次或每9周1次给药。
在一些实施方案中，所述抗CTLA-4抗体的给药方案包括给药期I和给药期II；其中：
(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为3.5-10mg/kg/次；
(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为0.5-3.5mg/kg。
在一些实施方案中，所述抗CTLA-4抗体的给药方案包括给药期I和给药期II；其中：
(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为约3.5mg/kg/次、约4mg/kg/次、约4.5mg/kg/次、约5mg/kg/次、约5.5mg/kg/次、约6mg/kg/次或约8mg/kg/次；
(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为约0.5mg/kg，约1.0mg/kg，约1.5mg/kg，约2mg/kg，约2.5mg/kg，约3.0mg/kg或约3.5mg/kg。
在一些实施方案中，所述抗CTLA-4抗体的给药方案包括给药期I和给药期II；其中：
(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为3.5-10mg/kg/次；
(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为30-150mg。
在一些实施方案中，所述抗CTLA-4抗体的给药方案包括给药期I和给药期II；其中：
(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为约3.5mg/kg/次、约4mg/kg/次、约4.5mg/kg/次、约5mg/kg/次、约5.5mg/kg/次、约6mg/kg/次或约8mg/kg/次；
(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为约30mg，约50mg，约60mg，约65mg，约70mg，约75mg，约80mg，约90mg，约100mg，约120mg，或约150mg。
在一些实施方案中，所述抗CTLA-4抗体的给药方案包括给药期I和给药期II；其中：
(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为220-360mg/次；
(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为30-150mg。
在一些实施方案中，所述抗CTLA-4抗体的给药方案包括给药期I和给药期II；其中：
(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为约220mg/次，约240mg/次，约260mg/次，约270mg/次，约280mg/次，约290mg/次，约300mg/次，约320mg/次，约340mg/次，或约360mg/次；
(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为约30mg，约50mg，约60mg，约65mg，约70mg，约75mg，约80mg，约90mg，约100mg，约120mg，或约150mg。
在一些实施方案中，所述抗CTLA-4抗体的给药方案包括给药期I和给药期II；其中：
(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为220-360mg/次；
(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为0.5-3.5mg/kg。
在一些实施方案中，所述抗CTLA-4抗体的给药方案包括给药期I和给药期II；其中：
(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为约220mg/次，约240mg/次，约260mg/次，约270mg/次，约280mg/次，约290mg/次，约300mg/次，约320mg/次，约340mg/次，或约360mg/次；
(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为约0.5mg/kg，约1.0mg/kg，约1.5mg/kg，约2mg/kg，约2.5mg/kg，约3.0mg/kg或约3.5mg/kg。
在一些实施方案中，所述给药期I为至少8周、至少10周、至少12周。在一些实施方案中，所述给药期I为8周、10周、12周、14周、16周、20周、24周、30周等。
本公开中给药期I和给药期II的时间可以由临床治疗效果
在一些实施方案中，所述抗CTLA-4抗体的给药方案选自：
给药剂量为约4.0mg/kg或约280mg，给药一次或两次；
给药剂量为约1.0mg/kg，每3周1次、每6周1次或每9周1次给药；
在给药期I给药一次，给药剂量为约4.0mg/kg；然后，在给药期II每6周1次给药，给药剂量为约1.0mg/kg；
在给药期I给药一次，给药剂量为约280mg；然后，在给药期II每6周1次给药，给药剂量为约70mg；
在给药期I给药两次，给药剂量为约4.0mg/kg/次；然后，在给药期II每6周1次给药，给药剂量为约1.0mg/kg；
或者，
在给药期I给药两次，给药剂量为约280mg/次；然后，在给药期II每6周1次给药，给药剂量为约70mg。
在一些实施方案中，在给药期I，抗CTLA-4抗体给药两次；并且，两次给药的时间间隔为≥4周，或≥6周，例如，4-20周，5-15周，6-12周。
<抗PD-L1抗体联合抗CTLA-4抗体>
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案为：
(a)抗CTLA-4抗体给药剂量为0.1-50mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为50-5000mg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体给药剂量为0.5-10mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为50-5000mg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体给药剂量为5-1000mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为50-5000mg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体给药剂量为100-400mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为50-5000mg，给药频率为每3周1次或每4周1次。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案为：
(a)抗CTLA-4抗体给药剂量为0.1-50mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为1-500mg/kg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体给药剂量为0.5-10mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为1-500mg/kg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体给药剂量为5-1000mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为1-500mg/kg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体给药剂量为100-400mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为1-500mg/kg，给药频率为每3周1次或每4周1次。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案为：
(a)抗CTLA-4抗体给药剂量为0.1-50mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体给药剂量为0.5-10mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体给药剂量为5-1000mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体给药剂量为100-400mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案为：
(a)抗CTLA-4抗体给药剂量为0.1-50mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体给药剂量为0.5-10mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体给药剂量为5-1000mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体给药剂量为100-400mg/kg，给药一次或多次；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案为：
(a)抗CTLA-4抗体的给药剂量为3.5-10mg/kg，给药一次或两次；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或(a)抗CTLA-4抗体的给药剂量为约3.5mg/kg、约4mg/kg、约4.5mg/kg、约5mg/kg、约5.5mg/kg或约6mg/kg，给药一次或两次；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或(a)抗CTLA-4抗体的给药剂量为220-360mg，给药一次或两次；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体的给药剂量为约220mg，约240mg，约260mg，约280mg，约300mg，约320mg，约340mg，或约360mg，给药一次或两次；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或(a)抗CTLA-4抗体的给药剂量为30-220mg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或(a)抗CTLA-4抗体的给药剂量为约30mg、约50mg、约60mg、约65mg、约70mg、约75mg、约80mg、约90mg、约100mg、约120mg、或约150mg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体的给药剂量为0.5-3.5mg/kg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体的给药剂量为约0.5mg/kg，约1.0mg/kg，约1.5mg/kg，约2mg/kg，约2.5mg/kg，约3.0mg/kg或约3.5mg/kg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体在给药期I的给药剂量为220-360mg，给药一次或两次；抗CTLA-4抗体在给药期II的给药剂量为30-220mg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体在给药期I的给药剂量为约220mg、约240mg、约260mg、约280mg、约300mg、约320mg、约340mg、或约360mg，给药一次或两次；抗CTLA-4抗体在给药期II的给药剂量为约30mg、约50mg、约60mg、约65mg、约70mg、约75mg、约80mg、约90mg、约100mg、约120mg、或约150mg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体在给药期I的给药剂量为3.5-10mg/kg，给药一次或两次；抗CTLA-4抗体在给药期II的给药剂量为0.5-3.5mg/kg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体在给药期I的给药剂量为约3.5mg/kg、约4mg/kg、约4.5mg/kg、约5mg/kg、约5.5mg/kg或约6mg/kg，给药一次或两次；抗CTLA-4抗体在给药期II的给药剂量为约0.5mg/kg、约1.0mg/kg、约1.5mg/kg、约2mg/kg、约2.5mg/kg、约3.0mg/kg或约3.5mg/kg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案为：
(a)抗CTLA-4抗体的给药剂量为3.5-10mg/kg，给药一次或两次；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或(a)抗CTLA-4抗体的给药剂量为约3.5mg/kg、约4mg/kg、约4.5mg/kg、约5mg/kg、约5.5mg/kg或约6mg/kg，给药一次或两次；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或(a)抗CTLA-4抗体的给药剂量为220-360mg，给药一次或两次；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体的给药剂量为约220mg，约240mg，约260mg，约280mg，约300mg，约320mg，约340mg，或约360mg，给药一次或两次；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或(a)抗CTLA-4抗体的给药剂量为30-220mg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或(a)抗CTLA-4抗体的给药剂量为约30mg、约50mg、约60mg、约65mg、约70mg、约75mg、约80mg、约90mg、约100mg、约120mg、或约150mg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体的给药剂量为0.5-3.5mg/kg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体的给药剂量为约0.5mg/kg，约1.0mg/kg，约1.5mg/kg，约2mg/kg，约2.5mg/kg，约3.0mg/kg或约3.5mg/kg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体在给药期I的给药剂量为220-360mg，给药一次或两次；抗CTLA-4抗体在给药期II的给药剂量为30-220mg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体在给药期I的给药剂量为约220mg、约240mg、约260mg、约280mg、约300mg、约320mg、约340mg、或约360mg，给药一次或两次；抗CTLA-4抗体在给药期II的给药剂量为约30mg、约50mg、约60mg、约65mg、约70mg、约75mg、约80mg、约90mg、约100mg、约120mg、或约150mg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体在给药期I的给药剂量为3.5-10mg/kg，给药一次或两次；抗CTLA-4抗体在给药期II的给药剂量为0.5-3.5mg/kg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或，(a)抗CTLA-4抗体在给药期I的给药剂量为约3.5mg/kg、约4mg/kg、约4.5mg/kg、约5mg/kg、约5.5mg/kg或约6mg/kg，给药一次或两次；抗CTLA-4抗体在给药期II的给药剂量为约0.5mg/kg、约1.0mg/kg、约1.5mg/kg、约2mg/kg、约2.5mg/kg、约3.0mg/kg或约3.5mg/kg，每3周1次、每6周1次或每9周1次给药；和，(b)抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案为：
(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为3.5-10mg/kg/次；(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为0.5-3.5mg/kg；和，(b)抗PD-L1抗体的给药剂量为50-5000mg，给药频率为每3周1次或每4周1次。
或，(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为220-360mg/次，(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为30-150mg；和，(b)抗PD-L1抗体的给药剂量为50-5000mg，给药频率为每3周1次或每4周1次。
或，(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为3.5-10mg/kg/次；(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为0.5-3.5mg/kg；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为约3.5mg/kg/次、约4mg/kg/次、约4.5mg/kg/次、约5mg/kg/次、约5.5mg/kg/次、约6mg/kg/次或约8mg/kg/次；(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为0.5mg/kg，约1.0mg/kg，约1.5mg/kg，约2mg/kg，约2.5mg/kg，约3.0mg/kg或约3.5mg/kg；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为220-360mg/次，(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为30-150mg；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，(a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为约220mg/次，约240mg/次，约260mg/次，约270mg/次，约280mg/次，约290mg/次，约300mg/次，约320mg/次，约340mg/次，或约360mg/次，(a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为约30mg，约50mg，约60mg，约65mg，约70mg，约75mg，约80mg，约90mg，约100mg，约120mg，或约150mg；和，(b)抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案为：
抗CTLA-4抗体的给药剂量为约4.0mg/kg或约280mg，给药一次或两次；和，抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，抗CTLA-4抗体的给药剂量为约1.0mg/kg，每3周1次、每6周1次或每9周1次给药；和，抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，在给药期I给药一次或两次，抗CTLA-4抗体的给药剂量为约4.0mg/kg/次；然后，在给药期II每6周1次给药，抗CTLA-4抗体的给药剂量为约1.0mg/kg；和，抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
或，在给药期I给药一次或两次，抗CTLA-4抗体的给药剂量为约280mg/次；然后，在给药期II每6周1次给药，抗CTLA-4抗体的给药剂量为约70mg。和，抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次或每4周1次。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案为：
抗CTLA-4抗体的给药剂量为约4.0mg/kg或约280mg，给药一次或两次；和，抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或，抗CTLA-4抗体的给药剂量为约1.0mg/kg，每3周1次、每6周1次或每9周1次给药；和，抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或，在给药期I给药一次或两次，抗CTLA-4抗体的给药剂量为约4.0mg/kg/次；然后，在给药期II每6周1次给药，抗CTLA-4抗体的给药剂量为约1.0mg/kg；和，抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
或，在给药期I给药一次或两次，抗CTLA-4抗体的给药剂量为约280mg/次；然后，在给药期II每6周1次给药，抗CTLA-4抗体的给药剂量为约70mg。和，抗PD-L1抗体的给药剂量为约20mg/kg，给药频率为每3周1次或每4周1次。
在一些实施方案中，给药期I，抗CTLA-4抗体给药的时间间隔为6-12周。
在一些实施方案中，所述抗CTLA-4抗体的给药方式为静脉注射给药。
通过本公开所提供的给药方案向受试者施用抗CTLA-4抗体和抗PD-L1抗体，可以显著提高肿瘤患者的客观缓解率(ORR)、延长无进展生存期(PFS)和/或总生存期(OS)，为肿瘤患者提供安全、有效的治疗方案,带来优于现有治疗的临床获益。
在一些实施方案中，所述抗PD-L1抗体、抗CTLA-4抗体进一步联合化疗剂、具有抗肿瘤活性的抗体和/或抗体药物偶联物、和/或抗血管生成剂。
“抗肿瘤活性”是指对肿瘤细胞的细胞毒活性、杀细胞效果，可通过在体外(invitro)测定抑制细胞增殖的抑制活性来确认。例如，可培养过量表达了抗体或抗体药物偶联物的靶标蛋白质的癌细胞株，向培养体系中添加各种浓度的抗体或抗体药物偶联物，测定针对灶点形成(focus formation)、集落(colony)形成及球体生长(spheroid growth)的抑制活性。可通过在体内(In vivo)，例如向移植了高表达靶标蛋白质的肿瘤细胞株的裸鼠(nude mouse)赋予抗体或抗体药物偶联物，测定癌细胞的变化，来确认抗肿瘤活性。
在一些实施方案中，所述化疗剂是基于肿瘤组织分型的含铂化疗。在一些实施方案中，所述化疗剂包括：铂类药物。在一些实施方案中，所述化疗剂包括：铂类药物和其他化疗药物。
在一些实施方案中，所述铂类药物为顺铂、和/或卡铂。
在一些实施方案中，其他化疗剂包括但不限于紫杉醇、白蛋白紫杉醇、培美曲塞、吉西他滨中的一种或多种。
在一些实施方案中，化疗剂包括如下任一种组合：1)卡铂或顺铂，培美曲塞；2)卡铂或顺铂，紫杉醇；3)卡铂或顺铂，白蛋白紫杉醇；4)吉西他滨，和顺铂。
在一些实施方案中，化疗剂可以是肿瘤化疗方案中，本领域技术人员所知晓的化疗药物的组合。例如，化疗剂可以是NCCN指南、CSCO指南中推荐的化疗方案中的药物组合。
在一些实施方案中，前述化疗剂按照治疗指南(例如，NCCN或CSCO)所推荐的给药方案施用于受试者。
在一些实施方案中，所述抗血管生成剂为抗VEGF抗体和/或抗VEGFR抗体。
在一些实施方案中，所述抗血管生成剂为贝伐珠单抗。
在一些实施方案中，所述抗VEGF抗体包含重链可变区(VH)和轻链可变区(VL)，其中所述重链可变区包含如SEQ ID NO:21-23所示的HCDR1、HCDR2和HCDR3，所述轻链可变区包含如SEQ ID NO:24-26所示的LCDR1、LCDR2和LCDR3。
其中，前面所述的各CDR序列如下表所示：
表3.抗VEGF抗体的CDR序列
上述的CDR是根据Kabat、IMGT、Chothia、AbM或Contact定义方案定义的。在一些具体的实施方案中，所述CDR是根据Kabat定义方案定义的。
在一些实施方案中，抗VEGF抗体包含重链可变区(VH)和轻链可变区(VL)：其中所述重链可变区包含如SEQ ID NO:21-23所示的HCDR1、HCDR2和HCDR3，所述轻链可变区包含如SEQ ID NO:24-26所示的LCDR1、LCDR2和LCDR3。
在一些实施方案中，抗VEGF抗体包含重链可变区(VH)和轻链可变区(VL)：，所述VH包含如SEQ ID NO:27所示序列中的HCDR1、HCDR2和HCDR3，所述VH包含如SEQ ID NO:28所示序列中的LCDR1、LCDR2和LCDR3。
在一些实施方案中，抗VEGF抗体包含前述HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3中的任意1个、2个、3个、4个、5个或6个。
在一些实施方案中，抗VEGF抗体为嵌合、人源化、全人抗体或其抗原结合片段。
在一些实施方案中，抗VEGF抗体，所述重链可变区包含如SEQ ID NO:27所示的氨基酸序列，或与之具有至少80％、90％序列同一性的氨基酸序列；轻链可变区包含如SEQ ID NO:28所示的氨基酸序列，或与之具有至少80％、90％序列同一性的氨基酸序列。
重链可变区：
轻链可变区：
在一些实施方案中，抗VEGF抗体进一步包含重链恒定区和/或轻链恒定区，例如，所述抗体恒定区的重链恒定区选自人IgG1、IgG2、IgG3和IgG4恒定区及其变体；所述抗体恒定区的轻链恒定区选自人抗体κ和λ链恒定区及其变体。
在一些实施方案中，抗VEGF抗体包含重链和轻链，所述重链包含如SEQ ID NO:29所示或与之具有至少80％、至少90％序列同一性的氨基酸序列；和/或，所述轻链包含如SEQ ID NO:30所示或与之具有至少80％、至少90％同一性的氨基酸序列。
在一些实施方案中，抗VEGF抗体包含如SEQ ID NO:29所示氨基酸序列的重链，和如SEQ ID NO:30所示氨基酸序列的轻链。
抗VEGF抗体的重链序列：
抗VEGF抗体的轻链序列：
注：划线部分为抗体重链或轻链的可变区序列，未划线部分为抗体恒定区序列。
在一些实施方案中，所述抗VEGF抗体的给药剂量为约0.5mg/kg至约500mg/kg，约1mg/kg至约50mg/kg，约5mg/kg至约50mg/kg，约5mg/kg至约30mg/kg，或约10mg/kg至约30mg/kg；约1.0mg/kg至约30mg/kg，约2.0mg/kg至约30mg/kg，约8.0mg/kg至约30mg/kg，约10mg/kg至约30mg/kg，约1.0mg/kg至约20mg/kg，约2.0mg/kg至约20mg/kg，约8.0mg/kg至约20mg/kg，约10mg/kg至约20mg/kg；或者为这些点值之间的任意范围。
在一些实施方案中，所述抗VEGF抗体的给药剂量选自约2.0mg/kg，约3.0mg/kg，约4.0mg/kg，约5.0mg/kg，约6.0mg/kg，约6.5mg/kg，约7.0mg/kg，约7.5mg/kg，8.0mg/kg，8.5mg/kg，约9.0mg/kg，约9.5mg/kg，约10.0mg/kg，约10.5mg/kg，约11.0mg/kg，约11.5mg/kg，约12.0mg/kg，约12.5mg/kg，约13.0mg/kg，约13.5mg/kg，约14.0mg/kg，约14.5mg/kg，约15.0mg/kg，约15.5mg/kg，约16.0mg/kg，约16.5mg/kg，约17.0mg/kg，约18.0mg/kg，约19.0mg/kg，约20.0mg/kg，约21.0mg/kg，约22.0mg/kg，约23.0mg/kg，约24.0mg/kg，约25.0mg/kg，约30.0mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约55mg/kg、约60mg/kg、约65mg/kg、约70mg/kg、约75mg/kg、约80mg/kg、约85mg/kg、约90mg/kg、约95mg/kg、约110mg/kg、约120mg/kg、约130mg/kg、约140mg/kg、约150mg/kg、约200mg/kg。或者为这些点值之间的任意数值范围。
在一些实施方案中，所述抗VEGF抗体的给药频率为1周1次，2周1次，3周1次，4周1次，6周1次，8周1次，10周1次，或12周1次。在一些具体的实施方案中，所述抗VEGF抗体药物偶联物的给药频率为3周1次。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案选自：
(1)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(4mg/kg，C1给药一次，C5给药一次)，和基于肿瘤组织分型的含铂化疗；
(2)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(280mg，C1给药一次，C5给药一次)，和基于肿瘤组织分型的含铂化疗；
(3)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(4mg/kg，C1给药一次)，和基于肿瘤组织分型的含铂化疗；
(4)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(280mg，C1给药一次)，和基于肿瘤组织分型的含铂化疗；
(5)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(1mg/kg，Q6W)，和基于肿瘤组织分型的含铂化疗；
(6)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(C1给药一次或两次，4mg/kg/次；C5开始以1mg/kg、Q6W持续给药)，和基于肿瘤组织分型的含铂化疗；
(7)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(C1给药一次或两次，280mg/次；C5开始以70mg、Q6W持续给药)，和基于肿瘤组织分型的含铂化疗。
示例性的，以2周、3周或4周为1个治疗周期，C1为第一个治疗周期，C5为第5个治疗周期。在一些具体的实施方案中，以3周为一个治疗周期。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案选自：
(1)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(4mg/kg，C1给药一次，C5给药一次)，和基于肿瘤组织分型的含铂化疗；
(2)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(280mg，C1给药一次，C5给药一次)，和基于肿瘤组织分型的含铂化疗；
(3)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(4mg/kg，C1给药一次)，和基于肿瘤组织分型的含铂化疗；
(4)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(280mg，C1给药一次)，和基于肿瘤组织分型的含铂化疗；
(5)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(1mg/kg，Q6W)，和基于肿瘤组织分型的含铂化疗；
(6)抗PD-L1抗体1200mg，Q3W)，抗CTLA-4抗体(C1给药一次或两次，4mg/kg/次；C5开始以1mg/kg、Q6W持续给药)，和基于肿瘤组织分型的含铂化疗；
(7)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(C1给药一次或两次，280mg/次；C5开始以70mg、Q6W持续给药)，和基于肿瘤组织分型的含铂化疗。
(8)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(4mg/kg，C1给药一次，C5给药一次)；
(9)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(280mg，C1给药一次，C5给药一次)，和基于肿瘤组织分型的含铂化疗；
(10)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(4mg/kg，C1给药一次)，和基于肿瘤组织分型的含铂化疗；
(11)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(280mg，C1给药一次)，和基于肿瘤组织分型的含铂化疗；
(12)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(1mg/kg，Q6W)，和基于肿瘤组织分型的含铂化疗；
(13)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(C1给药一次或两次，4mg/kg/次；C5开始以1mg/kg、Q6W持续给药)，和基于肿瘤组织分型的含铂化疗；
(14)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(C1给药一次或两次，280mg/次；C5开始以70mg、Q6W持续给药)，和基于肿瘤组织分型的含铂化疗。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案选自：
(1)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(4mg/kg，C1给药一次，C5给药一次)；
(2)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(280mg，C1给药一次，C5给药一次)；
(3)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(4mg/kg，C1给药一次)；
(4)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(280mg，C1给药一次)；
(5)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(1mg/kg，Q6W)；
(6)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(C1给药一次或两次，4mg/kg/次；C5开始以1mg/kg、Q6W持续给药)；
(7)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(C1给药一次或两次，280mg/次；C5开始以70mg、Q6W持续给药)。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案选自：
(1)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(4mg/kg，C1给药一次，C5给药一次)；
(2)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(280mg，C1给药一次，C5给药一次)；
(3)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(4mg/kg，C1给药一次)；
(4)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(280mg，C1给药一次)；
(5)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(1mg/kg，Q6W)；
(6)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(C1给药一次或两次，4mg/kg/次；C5开始以1mg/kg、Q6W持续给药)；
(7)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(C1给药一次或两次，280mg/次；C5开始以70mg、Q6W持续给药)。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体的给药方案选自：
(1)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(4mg/kg，C1给药一次，C5给药一次)；
(2)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(280mg，C1给药一次，C5给药一次)；
(3)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(4mg/kg，C1给药一次)；
(4)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(280mg，C1给药一次)；
(5)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(1mg/kg，Q6W)；
(6)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(C1给药一次或两次，4mg/kg/次；C5开始以1mg/kg、Q6W持续给药)；
(7)抗PD-L1抗体(1800mg，Q4W)，抗CTLA-4抗体(C1给药一次或两次，280mg/次；C5开始以70mg、Q6W持续给药)。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体、抗VEGF抗体的给药方案选自：
(1)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(4mg/kg，C1给药一次，C5给药一次)，抗VEGF抗体(15mg/kg，Q3W)；
(2)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(280mg，C1给药一次，C5给药一次)，抗VEGF抗体(15mg/kg，Q3W)；
(3)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(4mg/kg，C1给药一次)，抗VEGF抗体(15mg/kg，Q3W)；
(4)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(280mg，C1给药一次)；
(5)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(1mg/kg，Q6W)，抗VEGF抗体(15mg/kg，Q3W)；
(6)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(C1给药一次或两次，4mg/kg/次；C5开始以1mg/kg、Q6W持续给药)，抗VEGF抗体(15mg/kg，Q3W)；
(7)抗PD-L1抗体(20mg/kg，Q3W)，抗CTLA-4抗体(C1给药一次或两次，280mg/次；C5开始以70mg、Q6W持续给药)，抗VEGF抗体(15mg/kg，Q3W)。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体、抗VEGF抗体的给药方案选自：
(1)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(4mg/kg，C1给药一次，C5给药一次)，抗VEGF抗体(15mg/kg，Q3W)；
(2)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(280mg，C1给药一次，C5给药一次)，抗VEGF抗体(15mg/kg，Q3W)；
(3)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(4mg/kg，C1给药一次)，抗VEGF抗体(15mg/kg，Q3W)；
(4)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(280mg，C1给药一次)；
(5)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(1mg/kg，Q6W)，抗VEGF抗体(15mg/kg，Q3W)；
(6)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(C1给药一次或两次，4mg/kg/次；C5开始以1mg/kg、Q6W持续给药)，抗VEGF抗体(15mg/kg，Q3W)；
(7)抗PD-L1抗体(1200mg，Q3W)，抗CTLA-4抗体(C1给药一次或两次，280mg/次；C5开始以70mg、Q6W持续给药)，抗VEGF抗体(15mg/kg，Q3W)。
在一些实施方案中，抗PD-L1抗体联合抗CTLA-4抗体、抗VEGF抗体的给药方案选自：
(1)抗PD-L1抗体(1800mg/kg，Q4W)，抗CTLA-4抗体(4mg/kg，C1给药一次，C5给药一次)，抗VEGF抗体(15mg/kg，Q3W)；
(2)抗PD-L1抗体(1800mg/kg，Q4W)，抗CTLA-4抗体(280mg，C1给药一次，C5给药一次)，抗VEGF抗体(15mg/kg，Q3W)；
(3)抗PD-L1抗体(1800mg/kg，Q4W)，抗CTLA-4抗体(4mg/kg，C1给药一次)，抗VEGF抗体(15mg/kg，Q3W)；
(4)抗PD-L1抗体(1800mg/kg，Q4W)，抗CTLA-4抗体(280mg，C1给药一次)；
(5)抗PD-L1抗体(1800mg/kg，Q4W)，抗CTLA-4抗体(1mg/kg，Q6W)，抗VEGF抗体(15mg/kg，Q3W)；
(6)抗PD-L1抗体(1800mg/kg，Q4W)，抗CTLA-4抗体(C1给药一次或两次，4mg/kg/次；C5开始以1mg/kg、Q6W持续给药)，抗VEGF抗体(15mg/kg，Q3W)；
(7)抗PD-L1抗体(1800mg/kg，Q4W)，抗CTLA-4抗体(C1给药一次或两次，280mg/次；C5开始以70mg、Q6W持续给药)，抗VEGF抗体(15mg/kg，Q3W)。
在一些实施方案中，所述抗CTLA-4抗体、抗PD-L1抗体联合化疗剂。在一些实施方案中，化疗剂选自嘧啶类抗肿瘤药物和/或铂类药物；在一些实施方案中，嘧啶类抗肿瘤药物选自吉西他滨，铂类药物选自顺铂、卡铂、奈达铂、奥沙利铂或洛铂；在一些具体的实施方案中，铂类药物选自顺铂和/或卡铂。
在一些实施方案中，所述吉西他滨的给药剂量选自约50-2000mg/m2、约100-1500mg/m2、约400mg/m2、约500mg/m2、约600mg/m2、约700mg/m2，约800mg/m2、约900mg/m2、约1000mg/m2、约1100mg/m2、约1200mg/m2，约1300mg/m2、约1400mg/m2。
在一些实施方案中，所述吉西他滨的给药剂量选自约900mg/m2、约910mg/m2、约920mg/m2、约930mg/m2、约940mg/m2、约950mg/m2、约960mg/m2、约970mg/m2、约980mg/m2、约990mg/m2、约1000mg/m2、约1100mg/m2、约1200mg/m2、约1300mg/m2、约1400mg/m2、约1500mg/m2、约1600mg/m2、约1700mg/m2、约1800mg/m2、约1900mg/m2、约2000mg/m2，或前述任意两者之间的任意范围。
在一些实施方案中，所述吉西他滨的给药频率为每2周1次、每3周1次、每4周1次、每5周1次、或每6周1次。在一些具体的实施方案中，所述吉西他滨的给药频率为每3周1次。
在一些实施方案中，所述吉西他滨的给药剂量约950mg/m2、约960mg/m2、约970mg/m2、约980mg/m2、约990mg/m2、约1000mg/m2、约1100mg/m2、约1200mg/m2、约1300mg/m2、约1400mg/m2、约1500mg/m2，给药频率为每2周1次、每3周1次、每4周1次、每5周1次、或每6周1次。
在一些实施方案中，所述吉西他滨的给药剂量为约950-1500mg/m2，给药频率为每2周1次、每3周1次、每4周1次、每5周1次、或每6周1次。
在一些实施方案中，所述吉西他滨的给药剂量为约960-1400mg/m2，给药频率为每2周1次、每3周1次、每4周1次、每5周1次、或每6周1次。
在一些实施方案中，所述吉西他滨的给药剂量为约980-1200mg/m2，给药频率为每2周1次、每3周1次、每4周1次、每5周1次、或每6周1次。
在一些具体的实施方案中，所述吉西他滨的给药剂量为约980-1200mg/m2，给药频率为每3周1次。
在一些具体的实施方案中，所述吉西他滨的给药剂量为约980mg/m2，给药频率为每3周1次。
在一些实施方案中，所述吉西他滨的给药剂量为约990mg/m2，给药频率为每3周1次。
在一些实施方案中，所述吉西他滨的给药剂量为约1000mg/m2，给药频率为每3周1次。
在一些实施方案中，所述吉西他滨的给药剂量为约1100mg/m2，给药频率为每3周1次。
在一些实施方案中，所述吉西他滨的给药剂量为约1200mg/m2，给药频率为每3周1次。
在一些实施方案中，吉西他滨的给药途径可以为经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射。在一些具体的实施方案中，吉西他滨的给药途径为静脉注射。
在一些实施方案中，所述顺铂的给药剂量为约1-100mg/m2、约5-80mg/m2、约5-70mg/m2、约5-60mg/m2、约5-50mg/m2。
示例性地，所述顺铂的给药剂量为约5mg/m2、约15mg/m2、约20mg/m2、约25mg/m2、约30mg/m2、约35mg/m2、约40mg/m2、约45mg/m2、约50mg/m2；或前述任意两者之间的任意范围。
在一些实施方案中，所述顺铂的给药频率为每2周1次、每3周1次、每4周1次、每5周1次、或每6周1次。在一些具体的实施方案中，所述顺铂的给药频率为每三周1次。
在一些实施方案中，所述顺铂的给药剂量为约1-100mg/m2，给药频率为每2周1次、每3周1次、每4周1次、每5周1次、或每6周1次。在一些具体的实施方案中，所述顺铂的给药剂量为约1-100mg/m2，给药频率为每3周1次。
在一些实施方案中，所述顺铂的给药剂量为约5-80mg/m2，给药频率为每2周1次、每3周1次、每4周1次、每5周1次、或每6周1次。在一些具体的实施方案中，所述顺铂的给药剂量为约5-80mg/m2，给药频率为每3周1次。
在一些实施方案中，所述顺铂的给药剂量为约5-70mg/m2，给药频率为每2周1次、每3周1次、每4周1次、每5周1次、或每6周1次。在一些具体的实施方案中，所述顺铂的给药剂量为约5-70mg/m2，给药频率为每3周1次。
在一些实施方案中，所述顺铂的给药剂量为约5-60mg/m2，给药频率为每2周1次、每3周1次、每4周1次、每5周1次、或每6周1次。在一些具体的实施方案中，所述顺铂的给药剂量为约5-60mg/m2，给药频率为每3周1次。
在一些实施方案中，所述顺铂的给药剂量为约5-50mg/m2，给药频率为每2周1次、每3周1次、每4周1次、每5周1次、或每6周1次。在一些具体的实施方案中，所述顺铂的给药剂量为约5-50mg/m2，给药频率为每3周1次。
在一些实施方案中，所述顺铂的给药剂量为约20mg/m2，约21mg/m2，约22mg/m2，约23mg/m2，约24mg/m2，约25mg/m2，约26mg/m2，约27mg/m2，约28mg/m2，约29mg/m2，或约30mg/m2；给药频率为每3周1次。
在一些实施方案中，顺铂的给药途径可以为经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射。在一些具体的实施方案中，顺铂的给药途径为静脉注射。
在一些实施方案中，抗CTLA-4抗体联合抗PD-L1抗体的给药方案为如下任一项：
(1)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期(也即，给药期I)施用第一剂量的抗CTLA-4抗体，第二治疗周期(也即，给药期II)施用第二剂量的抗CTLA-4抗体；所述第一剂量的抗CTLA-4抗体为约60-500mg，第二剂量的抗CTLA-4抗体为约1-150mg；和，
所述抗PD-L1抗体的给药剂量为约50-2000mg，给药频率为每周一次，每2周至少一次，每3周至少一次，每4周至少一次，每6周至少一次，每8周至少一次或每10周至少一次；
(2)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期施用第一剂量的抗CTLA-4抗体，第二治疗周期施用第二剂量的抗CTLA-4抗体；第一剂量的抗CTLA-4抗体为约100-460mg，第二剂量的抗CTLA-4抗体为约20-130mg；和，
所述抗PD-L1抗体的给药剂量为约100-2000mg，给药频率为每周一次，每2周至少一次，每3周至少一次，每4周至少一次，每6周至少一次，每8周至少一次或每10周至少一次；
(3)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期施用第一剂量的抗CTLA-4抗体，第二治疗周期施用第二剂量的抗CTLA-4抗体；第一剂量的抗CTLA-4抗体为约160-400mg，第二剂量的抗CTLA-4抗体为约30-120mg；和，
所述抗PD-L1抗体的给药剂量为约200-2000mg，给药频率为每周一次，每2周至少一次，每3周至少一次，每4周至少一次，每6周至少一次，每8周至少一次或每10周至少一次；
(4)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期施用第一剂量的抗CTLA-4抗体，第二治疗周期施用第二剂量的抗CTLA-4抗体；第一剂量的抗CTLA-4抗体为约180-380mg，第二剂量的抗CTLA-4抗体为约50-100mg；和，
所述抗PD-L1抗体的给药剂量为约300-2000mg，给药频率为每3周1次；
(5)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期施用第一剂量的抗CTLA-4抗体，第二治疗周期施用第二剂量的抗CTLA-4抗体；第一剂量的抗CTLA-4抗体为约200-360mg，第二剂量的抗CTLA-4抗体为约60-90mg；和，
所述抗PD-L1抗体的给药剂量为约400-2000mg，给药频率为每3周1次；
(6)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期施用第一剂量的抗CTLA-4抗体，第二治疗周期施用第二剂量的抗CTLA-4抗体；第一剂量的抗CTLA-4抗体为约200mg、约220mg、约250mg、约260mg、约270mg、约280mg、约290mg、约300mg、约310mg、约320mg、约330mg、约340mg、约350mg、约360mg，第二剂量的抗CTLA-4抗体为约60mg、约70mg、约80mg、约90mg；和，
所述抗PD-L1抗体的给药剂量为约800mg、约850mg、约900mg、约950mg、约1000mg、约1050mg、约1100mg、约1150mg、约1200mg、约1250mg、约1300mg、约1350mg、约1400mg、约1450mg、约1500mg、约1550mg、约1600mg，给药频率为每3周1次；
(7)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期施用第一剂量的抗CTLA-4抗体，第二治疗周期施用第二剂量的抗CTLA-4抗体；第一剂量的抗CTLA-4抗体为约260mg、约265mg、约270mg、约275mg、约280mg、约285mg、约290mg、约295mg、约300mg，第二剂量的抗CTLA-4抗体为约60mg、约65mg、约70mg、约75mg、约80mg、约85mg、约90mg；和，
所述抗PD-L1抗体的给药剂量为约1000mg、约1050mg、约1100mg、约1150mg、约1200mg、约1250mg、约1300mg、约1350mg、约1400mg，给药频率为每3周1次；
(8)所述抗CTLA-4抗体的第一治疗周期为12周，在治疗周期的第一天施用第一剂量为约260mg、约265mg、约270mg、约275mg、约280mg、约285mg、约290mg、约295mg、约300mg的抗CTLA-4抗体，第二治疗周期每6周施用一次第二剂量约60mg、约65mg、约70mg、约75mg、约80mg、约85mg、约90mg的抗CTLA-4抗体；和，
所述抗PD-L1抗体的给药剂量为约1100mg、约1150mg、约1200mg、约1250mg、约1300mg，给药频率为每3周1次；
(9)所述抗CTLA-4抗体的第一治疗周期为12周，在治疗周期的第一天施用第一剂量为约270mg、约275mg、约280mg、约285mg、约290mg的抗CTLA-4抗体，第二治疗周期每6周施用一次第二剂量约65mg、约70mg、约75mg的抗CTLA-4抗体；和，
所述抗PD-L1抗体的给药剂量为约1150mg、约1200mg、约1250mg，给药频率为每3周1次；
(10)所述抗CTLA-4抗体的第一治疗周期为12周，在治疗周期的第一天施用第一剂量为约280mg的抗CTLA-4抗体，第二治疗周期每6周施用一次第二剂量为约70mg的抗CTLA-4抗体；和，
所述抗PD-L1抗体的给药剂量为约1180mg、约1200mg、约1220mg，给药频率为每3周1次。
在一些实施方案中，抗CTLA-4抗体联合抗PD-L1抗体、吉西他滨、顺铂的给药方案为如下任一项：
(1)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期施用第一剂量的抗CTLA-4抗体，第二治疗周期施用第二剂量的抗CTLA-4抗体；所述第一剂量的抗CTLA-4抗体为约60-500mg，第二剂量的抗CTLA-4抗体为约1-150mg；和，
所述抗PD-L1抗体的给药剂量为约50-2000mg，给药频率为每周一次，每2周至少一次，每3周至少一次，每4周至少一次，每6周至少一次，每8周至少一次或每10周至少一次；
所述吉西他滨的给药剂量选自约50-2000mg/m2，给药频率为每周一次，每2周至少一次，每3周至少一次，每4周至少一次，每6周至少一次，每8周至少一次或每10周至少一次；
所述顺铂的给药剂量为约1-100mg/m2，给药频率为每周一次，每2周至少一次，每3周至少一次，每4周至少一次，每6周至少一次，每8周至少一次或每10周至少一次；
(2)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期施用第一剂量的抗CTLA-4抗体，第二治疗周期施用第二剂量的抗CTLA-4抗体；第一剂量的抗CTLA-4抗体为约100-460mg，第二剂量的抗CTLA-4抗体为约20-130mg；和，
所述抗PD-L1抗体的给药剂量为约100-2000mg，给药频率为每周一次，每2周至少一次，每3周至少一次，每4周至少一次，每6周至少一次，每8周至少一次或每10周至少一次；
所述吉西他滨的给药剂量选自约950-1500mg/m2，给药频率为每周一次，每2周至少一次，每3周至少一次，每4周至少一次，每6周至少一次，每8周至少一次或每10周至少一次；
所述顺铂的给药剂量为约5-80mg/m2，给药频率为每周一次，每2周至少一次，每3周至少一次，每4周至少一次，每6周至少一次，每8周至少一次或每10周至少一次；
(3)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期施用第一剂量的抗CTLA-4抗体，第二治疗周期施用第二剂量的抗CTLA-4抗体；第一剂量的抗CTLA-4抗体为约160-400mg，第二剂量的抗CTLA-4抗体为约30-120mg；和，
所述抗PD-L1抗体的给药剂量为约200-2000mg，给药频率为每周一次，每2周至少一次，每3周至少一次，每4周至少一次，每6周至少一次，每8周至少一次或每10周至少一次；
所述吉西他滨的给药剂量选自约960-1400mg/m2，给药频率为每周一次，每2周至少一次，每3周至少一次，每4周至少一次，每6周至少一次，每8周至少一次或每10周至少一次；
所述顺铂的给药剂量为约5-70mg/m2，给药频率为每周一次，每2周至少一次，每3周至少一次，每4周至少一次，每6周至少一次，每8周至少一次或每10周至少一次；
(4)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期施用第一剂量的抗CTLA-4抗体，第二治疗周期施用第二剂量的抗CTLA-4抗体；第一剂量的抗CTLA-4抗体为约180-380mg，第二剂量的抗CTLA-4抗体为约50-100mg；和，
所述抗PD-L1抗体的给药剂量为约300-2000mg，给药频率为每3周1次；
所述吉西他滨的给药剂量选自约960-1400mg/m2，给药频率为每3周1次；
所述顺铂的给药剂量为约5-60mg/m2，给药频率为每3周1次；
(5)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期施用第一剂量的抗CTLA-4抗体，第二治疗周期施用第二剂量的抗CTLA-4抗体；第一剂量的抗CTLA-4抗体为约200-360mg，第二剂量的抗CTLA-4抗体为约60-90mg；和，
所述抗PD-L1抗体的给药剂量为约400-2000mg，给药频率为每3周1次；
所述吉西他滨的给药剂量选自约980-1200mg/m2，给药频率为每3周1次；
所述顺铂的给药剂量为约5-50mg/m2，给药频率为每3周1次；
(6)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期施用第一剂量的抗CTLA-4抗体，第二治疗周期施用第二剂量的抗CTLA-4抗体；第一剂量的抗CTLA-4抗体为约200mg、约220mg、约250mg、约260mg、约270mg、约280mg、约290mg、约300mg、约310mg、约320mg、约330mg、约340mg、约350mg、约360mg，第二剂量的抗CTLA-4抗体为约60mg、约70mg、约80mg、约90mg；和，
所述抗PD-L1抗体的给药剂量为约800mg、约850mg、约900mg、约950mg、约1000mg、约1050mg、约1100mg、约1150mg、约1200mg、约1250mg、约1300mg、约1350mg、约1400mg、约1450mg、约1500mg、约1550mg、约1600mg，给药频率为每3周1次；
所述吉西他滨的给药剂量选自约900mg/m2、约910mg/m2、约920mg/m2、约930mg/m2、约940mg/m2、约950mg/m2、约960mg/m2、约970mg/m2、约980mg/m2、约990mg/m2、约1000mg/m2、约1100mg/m2、约1200mg/m2、约1300mg/m2、约1400mg/m2、约1500mg/m2、约1600mg/m2、约1700mg/m2、约1800mg/m2、约1900mg/m2、约2000mg/m2，给药频率为每3周1次；
所述顺铂的给药剂量为约5mg/m2、约15mg/m2、约20mg/m2、约25mg/m2、约30mg/m2、约35mg/m2、约40mg/m2、约45mg/m2、约50mg/m2，给药频率为每3周1次；
(7)所述抗CTLA-4抗体采用可变给药周期，第一治疗周期施用第一剂量的抗CTLA-4抗体，第二治疗周期施用第二剂量的抗CTLA-4抗体；第一剂量的抗CTLA-4抗体为约260mg、约265mg、约270mg、约275mg、约280mg、约285mg、约290mg、约295mg、约300mg，第二剂量的抗CTLA-4抗体为约60mg、约65mg、约70mg、约75mg、约80mg、约85mg、约90mg；和，
所述抗PD-L1抗体的给药剂量为约1000mg、约1050mg、约1100mg、约1150mg、约1200mg、约1250mg、约1300mg、约1350mg、约1400mg，给药频率为每3周1次；
所述吉西他滨的给药剂量选自约950mg/m2、约960mg/m2、约970mg/m2、约980mg/m2、约990mg/m2、约1000mg/m2、约1100mg/m2、约1200mg/m2、约1300mg/m2、约1400mg/m2、约1500mg/m2，给药频率为每3周1次；
所述顺铂的给药剂量为约10mg/m2、约15mg/m2、约20mg/m2、约25mg/m2、约30mg/m2、约35mg/m2、约40mg/m2，给药频率为每3周1次；
(8)所述抗CTLA-4抗体的第一治疗周期为12周，在治疗周期的第一天施用第一剂量为260mg、约265mg、约270mg、约275mg、约280mg、约285mg、约290mg、约295mg、约300mg的抗CTLA-4抗体，第二治疗周期每6周施用一次第二剂量约60mg、约65mg、约70mg、约75mg、约80mg、约85mg、约90mg的抗CTLA-4抗体；和，
所述抗PD-L1抗体的给药剂量为约1100mg、约1150mg、约1200mg、约1250mg、约1300mg，给药频率为每3周1次；
所述吉西他滨的给药剂量选自约980mg/m2、约990mg/m2、约1000mg/m2、约1100mg/m2、约1200mg/m2，给药频率为每3周1次；
所述顺铂的给药剂量为约15mg/m2、约20mg/m2、约25mg/m2、约30mg/m2、约35mg/m2，给药频率为每3周1次；
(9)所述抗CTLA-4抗体的第一治疗周期为12周，在治疗周期的第一天施用第一剂量为约270mg、约275mg、约280mg、约285mg、约290mg的抗CTLA-4抗体，第二治疗周期每6周施用一次第二剂量约65mg、约70mg、约75mg的抗CTLA-4抗体；和，
所述抗PD-L1抗体的给药剂量为约1150mg、约1200mg、约1250mg，给药频率为每3周1次；
所述吉西他滨的给药剂量选自约990mg/m2、约1000mg/m2、约1100mg/m2，给药频率为每3周1次；
所述顺铂的给药剂量为约20mg/m2、约25mg/m2、约30mg/m2，给药频率为每3周1次；
(10)所述抗CTLA-4抗体的第一治疗周期为12周，在治疗周期的第一天施用第一剂量为约280mg的抗CTLA-4抗体，第二治疗周期每6周施用一次第二剂量为约70mg的抗CTLA-4抗体；和，
所述抗PD-L1抗体的给药剂量为约1180mg、约1200mg、约1220mg，给药频率为每3周1次；
所述吉西他滨的给药剂量选自约995mg/m2、约1000mg/m2、约1005mg/m2，给药频率为每3周1次；
所述顺铂的给药剂量为约23mg/m2、24mg/m2、约25mg/m2、约26mg/m2、约27mg/m2，给药频率为每3周1次。
在一些实施方案中，本公开中的抗CTLA-4抗体联合抗PD-L1抗体用于治疗胆道腺癌，表现出较好的安全性和积极的抗肿瘤活性。临床客观缓解率高，且具有降低的不良反应发生率、临床耐受性较好，有效提高患者生存时间。
一些实施方案中，接受本公开中治疗方案的肿瘤受试者具有显著改善的ORR、DoR、DCR、PFS和/或OS。
示例性地，ORR定义为按照RECIST v1.1评定最佳总体疗效(BOR)为CR或PR的受试者所占的比例。若疗效达CR、PR，受试者须在首次评价后不少于4周(28天)进行确认。最佳总体疗效是指研究者评定的最佳疗效，是自随机日期至按照RECIST v1.1客观记录疾病进展的日期或到开始用新的抗肿瘤治疗的日期(以先发生者为准)这段时间内记录的最佳疗效。
示例性地，DoR定义为从首次记录肿瘤缓解(按照RECIST v1.1评定)的日期到首次记录疾病进展的日期或因任何原因死亡的日期，以先发生者为准。
示例性地，DCR定义为按照RECIST v1.1评定最佳总体疗效为CR、PR和SD的受试者所占的比例。
示例性地，PFS定义为自随机日期开始，至第一次记录肿瘤进展(按照RECIST v 1.1评定，无论是否继续治疗)的日期或因任何原因死亡的日期，以先发生者为准。
示例性地，OS定义为自随机日期开始到因各种原因导致受试者死亡之间的时间。末次随访时仍存活的受试者，其OS以末次随访时间计为数据删失。失访的受试者，其OS以失访前末次证实存活时间计为数据删失。数据删失的OS定义为从随机到删失的时间。
附图说明
图1示出了实施例2中不同给药方案下肿瘤病灶的缓解情况。
术语
为了更容易理解本公开，以下具体定义了某些技术和科学术语。除非在本文中另有明确定义，本文使用的所有其它技术和科学术语都具有本公开所属领域的一般技术人员通常理解的含义。
除非上下文另外清楚要求，否则在整个说明书和权利要求书中，应将词语“包含”、“具有”、“包括”等理解为具有包含意义，而不是排他性或穷举性意义；也即，“包括但不仅限于”的意义。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。
“约”、“大约”是指数值在由本领域一般技术人员所测定的具体值的可接受误差范围内，所述数值部分取决于怎样测量或测定(即测量体系的限度)。例如，“约”可意味着在1内或超过1的标准差。或者，“约”或“基本上包含”可意味着至多20％的范围，例如1％至15％之间、在1％至10％之间、在1％至5％之间、在0.5％至5％之间、在0.5％至1％之间变化，本公开中，数字或数值范围之前有术语“约”的每种情况也包括给定数的实施方案。除非另外说明，否则当具体值在本申请和权利要求中出现时，“约”或“基本上包含”的含义应该假定为在该具体值的可接受误差范围内。
术语“和/或”，例如“X和/或Y”应当理解为意指“X和Y”或“X或Y”并且应当被用来提供对两种含义或任一含义的明确支持。
在一些实施方案中，本公开进行如下定义：
本公开中的“抗体-药物偶联物”表示将具有细胞毒性的药物经由连接子结合于抗体而成的复合体。作为本公开中使用的细胞毒性的药物，只要是具有抗肿瘤效果、且具有能连接于接头结构的取代基、部分结构的化合物即可，没有特别限制。对于细胞毒性的药物而言，接头的一部分或全部在肿瘤细胞内被切断，游离出抗肿瘤性化合物部分，从而显示抗肿瘤效果。在与药物的连接部分切断接头时，以未修饰的结构游离出抗肿瘤性化合物，可发挥其本来的抗肿瘤效果。
如果抗体药物偶联物在给定时间的生物活性是在制备药物制剂时表现出的生物活性的预定范围内，那么所述抗体药物偶联物在药物制剂中“保留它的生物活性”。
本公开所用氨基酸三字母代码和单字母代码如J.biol.chem，243，p3558(1968)中所述。
如本文所用，术语“抗体”以最广义使用，涵盖各种抗体结构，包括但不限于单克隆抗体，多克隆抗体；单特异性抗体，多特异性抗体(例如双特异性抗体)，全长抗体和抗体片段(或抗原结合片段，或抗原结合部分)，只要它们展现出期望的抗原结合活性。抗体可以指免疫球蛋白，是由两条相同的重链和两条相同的轻链通过链间二硫键连接而成的四肽链结构。免疫球蛋白重链恒定区的氨基酸组成和排列顺序不同，故其抗原性也不同。据此，可将免疫球蛋白分为五类，或称为免疫球蛋白的同种型，即IgM、IgD、IgG、IgA和IgE，其相应的重链分别为μ链、δ链、γ链、α链和ε链。同一类Ig根据其铰链区氨基酸组成和重链二硫键的数目和位置的差别，又可分为不同的亚类，如IgG可分为IgG1、IgG2、IgG3、IgG4。轻链通过恒定区的不同分为κ链或λ链。五类Ig中第每类Ig都可以有κ链或λ链。抗体重链和轻链靠近N端的约110个氨基酸的序列变化很大，为可变区(V区)；靠近C端的其余氨基酸序列相对稳定，为恒定区(C区)。可变区包括3个高变区(CDR)和4个序列相对保守的骨架区(FR)。3个高变区决定抗体的特异性，又称为互补性决定区(CDR)。每条轻链可变区(VL)和重链可变区(VH)由3个CDR区4个FR区组成，从氨基端到羧基端依次排列的顺序为：FR1，CDR1，FR2，CDR2，FR3，CDR3，FR4。轻链的3个CDR区指LCDR1，LCDR2，和LCDR3；重链的3个CDR区指HCDR1，HCDR2和HCDR3。
对于CDR的确定或定义，能够通过分辨抗体的结构和/或分辨抗体-配体复合物的结构来完成CDR的确定性描绘和包含抗体的结合位点的残基的鉴定。这可通过本领域技术人员已知的各种技术中的任一种，例如X射线晶体学来实现。多种分析方法可用于鉴定CDR，包括但不限于Kabat编号系统、Chothia编号系统、AbM编号系统、IMGT编号系统、接触定义、构象定义。
可以通过各种公知方案来确定CDR的氨基酸序列边界，例如：“Kabat”编号规则(参见Kabat等(1991)，“Sequences of Proteins of Immunological Interest”，第5版，Public Health Service，National Institutes of Health，Bethesda，MD)、“Chothia”编号规则、“ABM”编号规则、“contact”编号规则(参见Martin,ACR.Protein Sequence and Structure Analysis of Antibody Variable Domains[J].2001)和ImMunoGenTics(IMGT)编号规则(Lefranc，M.P.等，Dev.Comp.Immunol.，27，55-77(2003)；Front Immunol.2018Oct 16；9:2278)等。
术语“抗原结合片段”或“功能片段”或“抗原结合部分”是指保持特异性结合抗原的能力的完整抗体的一个或更多个片段。已显示可利用全长抗体的片段来进行抗体的抗原结合功能。示例性的，涵盖在术语“抗原结合片段”的结合片段的实例包括：(i)Fab片段，一种由VL、VH、CL和CH1结构域组成的单价片段；(ii)F(ab')2片段，一种包含通过铰链区上的二硫键桥连接的两个Fab片段的二价片段，(iii)由VH和CH1结构域组成的Fd片段；(iv)由抗体的单臂的VH和VL结构域组成的Fv片段；(v)dsFv，由VH和VL经链间二硫键形成的稳定的抗原结合片段；(vi)scFv；(vii)包含scFv、dsFv、Fab等片段的双抗体、双特异性抗体和多特异性抗体。
术语“特异性结合”、“选择性结合”、“选择性地结合”和“特异性地结合”是指抗体对预先确定的抗原上的表位的结合。通常，抗体以大约小于10-8M，例如大约小于10-9M、10-10M、10-11M或更小的亲和力(KD)结合。
术语"KD"是指特定抗体-抗原相互作用的解离平衡常数。通常，本公开的抗体以小于大约10-7M，例如小于大约10-8M、10-9M或10-10M或更小的解离平衡常数(KD)结合IL-5，例如，如使用表面等离子体共振(SPR)技术在BIACORE仪中测定的。
“同源性”是指两个多核苷酸序列之间或两个多肽之间的序列相似性。当两个比较序列中的位置均被相同碱基或氨基酸单体亚基占据时，例如如果两个DNA分子的每一个位置都被腺嘌呤占据时，那么所述分子在该位置是同源的。两个序列之间的同源性百分率是两个序列共有的匹配或同源位置数除以比较的位置数×100的函数。例如，在序列最佳比对时，如果两个序列中的10个位置有6个匹配或同源，那么两个序列为60％同源；如果两个序列中的100个位置有95个匹配或同源，那么两个序列为95％同源。通常，当比对两个序列时进行比较以给出最大百分比同源性。例如，可以通过BLAST算法执行比较，其中选择算法的参数以在各个参考序列的整个长度上给出各个序列之间的最大匹配。以下参考文献涉及经常用于序列分析的BLAST算法：BLAST算法(BLAST ALGORITHMS)：Altschul，S.F.等人，(1990)J.Mol.Biol.215:403-410；Gish，W.等人，(1993)Nature Genet.3:266-272；Madden，T.L.等人，(1996)Meth.Enzymol.266:131-141；Altschul，S.F.等人，
(1997)Nucleic Acids Res.25:3389-3402；Zhang，J.等人，(1997)Genome Res.7:649-656。其他如NCBI BLAST提供的常规BLAST算法也为本领域技术人员所熟知。
“给予”和“处理”当应用于动物、人、实验受试者、细胞、组织、器官或生物流体时，是指外源性药物、治疗剂、诊断剂或组合物与动物、人、受试者、细胞、组织、器官或生物流体的接触。“给予”和“处理”可以指例如治疗、药物代谢动力学、诊断、研究和实验方法。细胞的处理包括试剂与细胞的接触，以及试剂与流体的接触，其中所述流体与细胞接触。“给予”和“处理”还意指通过试剂、诊断、结合组合物或通过另一种细胞体外和离体处理例如细胞。“处理”当应用于人、兽医学或研究受试者时，是指治疗处理、预防或预防性措施，研究和诊断应用。
“治疗”意指给予患者内用或外用治疗剂，例如包含本公开的任一种结合化合物的组合物，所述患者具有一种或多种疾病症状，而已知所述治疗剂对这些症状具有治疗作用。通常，在受治疗患者或群体中以有效缓解一种或多种疾病症状的量给予治疗剂，以诱导这类症状退化或抑制这类症状发展到任何临床可测量的程度。有效缓解任何具体疾病症状的治疗剂的量(也称作“治疗有效量”)可根据多种因素变化，例如患者的疾病状态、年龄和体重，以及药物在患者产生需要疗效的能力。通过医生或其它专业卫生保健人士通常用于评价该症状的严重性或进展状况的任何临床检测方法，可评价疾病症状是否已被减轻。尽管本公开的实施方案(例如治疗方法或制品)在缓解每个目标疾病症状方面可能无效，但是根据本领域已知的任何统计学检验方法如Student t检验、卡方检验、依据Mann和Whitney的U检验、Kruskal-Wallis检验(H检验)、Jonckheere-Terpstra检验和Wilcoxon检验确定，其在统计学显著数目的患者中应当减轻目标疾病症状。
“有效量”包含足以改善或预防医学疾病的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：例如，待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
术语“受试者”、“患者”意指哺乳动物，尤其灵长类动物，尤其是人。
本公开所述的“联合”是一种给药方式，是指一定时间期限内给予至少一种剂量的抗PD-L1抗体，以及至少一种剂量的抗CTLA-4抗体，其中两种药物都显示药理学作用。所述的时间期限可以是一个给药周期内，例如4周内，3周内，2周内，1周内，或24小时以内，或12小时以内等。可以同时或依次给予抗PD-L1抗体和抗CTLA-4抗体和其他类的药物。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予抗PD-L1抗体和抗CTLA-4抗体。本公开所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非是对本公开范围的限制。本公开实施例中未注明具体条件的实验方法，通常按照常规条件，如参照冷泉港实验室出版的《抗体技术实验手册》，《分子克隆手册》；或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例1.抗CTLA-4抗体联合抗PD-L1抗体及抗VEGF抗体治疗肝细胞癌的开放、多中心的Ib/II临床研究
1.1试验药物
抗PD-L1抗体，其重链序列如SEQ ID NO:9所示，轻链序列如SEQ ID NO:10所示。剂型：注射剂，规格：600mg/12mL。
抗CTLA-4抗体，其重链序列如SEQ ID NO:19所示，轻链序列如SEQ ID NO:20所示。剂型：无菌注射剂，规格：50mg/10mL。
抗VEGF抗体，其重链序列如SEQ ID NO:29所示，轻链序列如SEQ ID NO:30所示。剂型：注射剂，规格：4mL：100mg。
1.2入组受试者
(1)第一阶段(剂量探索+剂量确认阶段)：经病理学确诊的、无法根治的晚期HCC患者，经标准治疗失败或不愿意接受标准治疗者；
(2)第二阶段(疗效扩展阶段)：经病理学确诊的无法根治的晚期HCC患者，既往未经免疫治疗(包括但不限于：PD-1/L1抑制剂，CTLA-4抑制剂)，且既往系统治疗线数≤1线。
(3)至少具有一个符合RECIST v1.1标准的可测量病灶(接受过局部治疗的病灶需出现明确进展，方可作为可测量病灶)；
(4)巴塞罗那临床分期(BCLC分期)：B期或C期；
(5)ECOGPS评分：0-1分；
(6)肝功能Child-Pugh分级评分：≤7分；
(7)预期的生存期≥3个月。
1.3研究方案
第一阶段(剂量探索+剂量确认阶段)：本阶段拟入组既往经标准治疗失败的晚期HCC患者。抗PD-L1抗体联合抗CTLA-4抗体给药；给药顺序：先给予抗PD-L1抗体，再给予抗CTLA-4抗体。
抗PD-L1抗体：20mg/kg，每3周1次(Q3W)，静脉注射(IV)；
抗CTLA-4抗体：1)1mg/kg，Q6W；或，2)4mg/kg，给药一次。
第二阶段(疗效扩展阶段)：本阶段的研究对象为既往未经免疫治疗(包括但不限于：PD-1/L1抑制剂，CTLA-4抑制剂)，且既往治疗线数≤1线的HCC患者。
(1)抗PD-L1抗体(20mg/kg，Q3W)+抗VEGF抗体(15mg/kg，Q3W)；
(2)抗PD-L1抗体(20mg/kg，Q3W)+抗VEGF抗体(15mg/kg，Q3W)+抗CTLA-4抗体(1mg/kg，Q6W)；
(3)抗PD-L1抗体(20mg/kg，Q3W)+抗VEGF抗体(15mg/kg，Q3W)+抗CTLA-4抗体(4mg/kg，C1给药一次)；
(4)抗PD-L1抗体(20mg/kg，Q3W)+抗VEGF抗体(15mg/kg，Q3W)+抗CTLA-4抗体(4mg/kg，C1及C5各给药一次)；
以每3周为一个治疗周期，C1是指第1个治疗周期，C5是指第5个治疗周期；并且，C1至C4对应给药期I，C5开始对应给药期II。
1.4结果评价
表4.1示出了接受两药或三药联用的受试者基线特征，其有效性评价结果如表4.2所示。由表4.2可知，本实施例提供的抗CTLA-4抗体、抗PD-L1抗体、抗VEGF抗体的三药联用方案较抗PD-L1抗体、抗VEGF抗体的两药联用方案可以明显提高完全缓解(CR)和部分缓解(PR)的患者比例，明显高肿瘤临床治疗的客观缓解率，患者可获得较好的临床获益。
表4.1受试者基线特征

表4.2疗效评价
截至2024年10月31日，联用1的中位随访时间为16.7个月，联用2的中位随访时间为11.1个月，联用3的中位随访时间为11.3个月。疗效评价结果如表4.3所示，在接受联用2中三药联合治疗的受试者中，客观缓解率(ORR)为47.2％(25/53；95％置信区间33.3％-61.4％)，中位缓解持续时间(DoR)为12.7个月(95％置信区间5.8-尚未达到)。与联用1组和联用2组相比，联用2组在数值上展现了更高的客观缓解率及更好的生存结局。安全性方面，三级以上(grade≥3)TRAEs(treatment-related adverse events)在联用1、联用2和联用3中发生率分别为55.6％,41.5％和42.9％，患者耐受良好。
表4.3疗效评价

实施例2.抗CTLA-4抗体联合抗PD-L1抗体及含铂化疗一线治疗晚期非小细胞肺癌的随机、开放、多中心的Ⅱ期临床研究
2.1试验药物
抗PD-L1抗体，其重链序列如SEQ ID NO:9所示，轻链序列如SEQ ID NO:10所示。剂型：注射剂，规格：600mg/12mL。
抗CTLA-4抗体，其重链序列如SEQ ID NO:19所示，轻链序列如SEQ ID NO:20所示。剂型：无菌注射剂，规格：50mg/10mL。
注射用培美曲塞二钠，规格：0.2g(以培美曲塞计)；
注射用紫杉醇(白蛋白结合型)，规格：100mg/瓶(以紫杉醇含量计算)；
紫杉醇注射液，规格：(1)5ml：30mg，(2)16.7ml：100mg；
注射用卡铂，规格：0.1g/支；
顺铂注射液，规格：6mL：30mg。
2.2入组受试者
(1)探索阶段(Ib期)：经病理学确诊的、无法根治的NSCLC，经标准治疗失败者；
(2)剂量确阶段(II期)：既往未经系统性治疗，经组织或细胞学确诊的复发或晚期NSCLC，中心实验室证实为PD-L1 TPS＜50％者。注：若既往接受过新辅助或辅助化疗/放疗，自治疗结束至复发或转移>6个月者可以入组。
(3)至少具有一个符合RECIST v1.1标准的可测量病灶(接受过放疗的病灶需出现明确进展，方可作为可测量病灶)。
(4)ECOGPS评分：0-1分。
(5)预期的生存期≥3个月。
2.3研究方案
第一阶段(Ib期)：抗PD-L1抗体联合抗CTLA-4抗体给药；给药顺序：先给予抗PD-L1抗体，再给予抗CTLA-4抗体。
抗PD-L1抗体：20mg/kg，每3周1次(Q3W)，静脉注射(IV)；
抗CTLA-4抗体：1)1mg/kg，Q6W；或，2)4mg/kg，给药一次。
第二阶段(II期)：
(1)抗PD-L1抗体(20mg/kg，Q3W)+抗CTLA-4抗体(1mg/kg，Q6W)+基于肿瘤组织分型的含铂化疗(非鳞癌：培美曲塞+卡铂/顺铂联合给药4个疗程，然后可选择培美曲塞单药维持，直至符合治疗结束标准；鳞癌：白蛋白紫杉醇/紫杉醇+卡铂/顺铂联合给药4个疗程)；
(2)抗PD-L1抗体(20mg/kg，Q3W)+抗CTLA-4抗体(4mg/kg，C1给药一次)+基于肿瘤组织分型的含铂化疗；
(3)抗PD-L1抗体(20mg/kg，Q3W)+抗CTLA-4抗体(4mg/kg，C1给药一次，C5给药一次)+基于肿瘤组织分型的含铂化疗；
(4)抗PD-L1抗体(1200mg，Q3W)+抗CTLA-4抗体(280mg，C1给药一次，C5起70mg、Q6W给药)+基于肿瘤组织分型的含铂化疗；
(5)抗PD-L1抗体(1200mg，Q3W)+基于肿瘤组织分型的含铂化疗。
随机分层因素为：1)PD-L1表达(PD-L1＜1％vs.1-49％)；2)组织分型(非鳞癌vs.鳞癌)对于非鳞NSCLC：培美曲塞500mg/m2+卡铂AUC 5mg/mL/min或顺铂75mg/m2联合给药4个疗程，后续可选培美曲塞维持；对于鳞状NSCLC，白蛋白紫杉醇100g/m2 D1，8，15或紫杉醇175mg/m2+卡铂/顺铂联合给药4个疗程。
2.4结果评价
表5.1示出了接受三药联用的受试者基线特征，其有效性评价结果如表5.2和图1所示。由表5.2和图1可知，本实施例提供的抗CTLA-4抗体联合抗PD-L1抗体、化疗的方案具有较好的完全缓解(CR)和部分缓解(PR)的患者比例，显著提高肿瘤临床治疗的客观缓解率，患者可获得较好的临床获益。
表5.1受试者基线特征

表5.2疗效评价
截止2025.06.03的更新数据结果显示(表5.3)，抗CTLA-4抗体联合抗PD-L1抗体、化疗的方案能够维持较好的客观缓解率，且中位缓解持续时间(median Duration of Response，mDoR)达到11.1个月，中位无进展生存期(mPFS)达到8.3，具有显著的临床获益。
表5.3疗效评价
实施例3.抗CTLA-4抗体联合抗PD-L1抗体及含铂化疗一线治疗晚期胆道癌的随机、开放、多中心的Ⅱ期临床研究
1、试验药物
(1)抗CTLA-4抗体：其重链序列为SEQ ID NO：9，轻链序列为SEQ ID NO：10。规格：50mg/10mL。
(2)抗PD-L1抗体：其重链序列为SEQ ID NO：23，轻链序列为SEQ ID NO：24。规格：12mL:0.6g。
(3)市售吉西他滨注射液；规格：1.0g；注射剂瓶，1瓶/盒。
(4)市售顺铂注射液；规格：6mL：30mg。
2、入组受试者
(1)年龄18～75周岁(含边界值，以签署知情同意当日计算)，男女均可；
(2)经组织学或细胞学确诊的不可手术切除的局部晚期、或复发/转移性胆道腺癌(包括胆囊癌、肝内胆管癌、肝外胆管癌)。
(3)既往未接受过系统性抗肿瘤治疗；若既往接受过新辅助/辅助放疗和(或)化疗，自治疗结束至复发或转移＞6个月者可以入组。
(4)至少有一个符合RECIST v1.1的可测量病灶(根据RECIST v1.1要求该可测量病灶螺旋CT扫描长径≥10mm或肿大淋巴结短径≥15mm)；经过局部治疗的病灶，如明确证据证实，较治疗结束后有显著进展，可选为靶病灶；
(5)ECOGPS评分：0–1分；
(6)预期的生存期≥3个月。
3、给药方案
抗PD-L1抗体：1200mg，静脉输注；每周期D1给药1次，每3周为一个治疗周期(Q3W)。
抗CTLA-4抗体：在第一治疗周期(每3周为一个治疗周期)的D1给药280mg，给药1次；自第五治疗周期开始，每2个周期D1给药1次，70mg(即70mg Q6W)。静脉输注。
吉西他滨注射液：1000mg/m2，静脉输注；每周期D1和D8各给药一次，每3周为一个周期(Q3W)；持续至肿瘤进展、不可耐受的毒性、或其它治疗结束标准。
顺铂注射液：25mg/m2，静脉滴注(需要水化用药)，慢速滴注；每周期D1和D8各给药一次，每3周为1个给药周期(Q3W)；给药至多8个周期。
队列A：接受抗PD-L1抗体+抗CTLA-4抗体+吉西他滨+顺铂治疗
队列B：接受抗PD-L1抗体+吉西他滨+顺铂治疗
给药顺序：根据研究流程设定在同一天给药的药物：应先给予抗PD-L1抗体，然后给予抗CTLA-4抗体，最后再给予含铂化疗。尽量在同一天内完成给药。
注：治疗期间，每周期D1给药前测量体重，若相比C1D1体重变化＜10％(增加或减少)，由研究者判断是否重新计算给药剂量；若相比C1D1体重改变≥10％(增加或减少)，则需要重新计算给药剂量。每周期D8给药采用的体重建议根据D1给药的体重测量值。重新计算给药剂量以后，后续体重变化与最近一次重新计算剂量所采用的体重相比。为方便给药，实际给药量较计划给药量可以接受±5％的误差。
4、有效性评价
表6示出患者的疗效评价结果，其中共入组(ITT集)80例晚期BTC患者，两组各随机40例。由表6数据可以看出，接受抗PD-L1抗体+抗CTLA-4抗体+吉西他滨+顺铂治疗的患者(队列A)客观缓解率(ORR)明显高于队列B。且队列A、队列B的中位无进展生存期分别为6.8个月、5.5个月，HR＝0.72(0.35-1.48)。患者具有显著的临床获益和良好的耐受性。
表6.疗效评价

实施例4.抗CTLA-4抗体联合抗PD-L1抗体及及含铂双药化疗一线治疗STK11/KEAP1/KRAS突变晚期或转移性非鳞状非小细胞肺癌的随机、开放、平行对照、多中心II/III期研究
4.1试验药物
抗PD-L1抗体，其重链序列如SEQ ID NO:9所示，轻链序列如SEQ ID NO:10所示。剂型：注射剂，规格：600mg/12mL。
抗CTLA-4抗体，其重链序列如SEQ ID NO:19所示，轻链序列如SEQ ID NO:20所示。剂型：无菌注射剂，规格：50mg/10mL。
注射用培美曲塞二钠，规格：0.2g(以培美曲塞计)；
注射用卡铂，规格：0.1g/支。
4.2入组受试者
1)经组织学或细胞学确诊的晚期或转移性非鳞状NSCLC受试者。晚期定义：按照国际肺癌研究协会(第8版TNM分期标准判断分期为ⅢB期期，且已不适合开展根治性手术或放疗治疗。
2)经中心实验室检测具有STK11、KEAP1、KRAS突变或共突变第一阶段可接受研究中心认可的检测结果。
3)针对局部晚期转移性非鳞状NSCLC未接受过化疗或其他系统性治疗，允许既往接受过辅助或新辅助治疗，但疾病进展需发生于末次治疗6个月以后。
4)入组前未接受过免疫介导治疗，包括但不限于抗CTLA-4、抗PD-1、抗PD-L1、抗PD-L2等抗体。
5)中枢神经系统之外至少具有一个符合RECIST v1.1标准定义的可测量病灶。
6)ECOG体力评分0-1分。
4.3研究方案
第一阶段(II期阶段)：主要目的是评估抗PD-L1抗体联合抗CTLA-4抗体及含铂双药化疗治疗STK11/KEAP1/KRAS突变或共突变的晚期或转移性非鳞状非小细胞肺癌受试者的有效性和安全性。
Arm A：抗PD-L1抗体+抗CTLA-4抗体+含铂双药化疗；其中：
抗PD-L1抗体，Q3W，1200mg，静脉滴注；
抗CTLA-4抗体，Q6W，1.0mg/kg，静脉滴注；诱导治疗阶段C1、C3、C5周期第一天各给药1次，维持治疗阶段C7周期第一天给药1次，总共用药4次；
培美曲塞，500mg/m2，静脉输注，每3周为1个给药周期，每周期第1天给药。
卡铂，AUC5mg/mL/min，静脉输注，每3周为1个给药周期，每周期第1天给药，给药4-6周期。
Arm D：抗PD-L1抗体+抗CTLA-4抗体+含铂双药化疗；其中：
抗PD-L1抗体，Q3W，1200mg，静脉滴注；
抗CTLA-4抗体，C1给药280mg，C5起每6周给药1次(Q6W)，每次给药剂量70mg，静脉滴注；
培美曲塞，500mg/m2，静脉输注，每3周为1个给药周期，每周期第1天给药；
卡铂，AUC5mg/mL/min，静脉输注，每3周为1个给药周期，每周期第1天给药，给药4-6周期。
第二阶段(III期阶段)：主要目的是评估抗PD-L1抗体联合抗CTLA-4抗体及含铂双药化疗作为一线治疗的有效性和安全性。接受抗PD-L1抗体联合抗CTLA-4抗体及含铂双药化疗。
4.4结果评价
基于研究者评估的客观缓解率(ORR)、基于研究者评估的缓解持续时间(DoR)、基于研究者评估的疾病控制率(DCR)、基于研究者评估的无进展生存期(PFS)、总生存期(OS)。
实施例5.抗CTLA-4抗体联合抗PD-L1抗体及及含铂双药化疗一线治疗肝细胞癌(HCC)的随机、开放、平行对照、多中心III期研究
5.1试验药物
抗PD-L1抗体，其重链序列如SEQ ID NO:9所示，轻链序列如SEQ ID NO:10所示。剂型：注射剂，规格：600mg/12mL。
抗CTLA-4抗体，其重链序列如SEQ ID NO:19所示，轻链序列如SEQ ID NO:20所示。剂型：无菌注射剂，规格：50mg/10mL。
注射用培美曲塞二钠，规格：0.2g(以培美曲塞计)；
注射用卡铂，规格：0.1g/支。
5.2入组受试者
1)病理组织学/细胞学证实的不可切除的局部晚期或转移性HCC。
2)巴萨罗那临床肝癌分期(BCLC分期，见附件1)B期或C期，且已不适合手术或局部治疗。
3)既往未接受过针对HCC的系统性抗肿瘤治疗，除外以下情况：
-允许新辅助/辅助阶段接受过小分子抗血管生成药物，如仑伐替尼、索拉非尼、多纳非尼等，但末次用药日期距离随机日期须≥90天；
-允许先前使用说明书中包含抗癌活性的中药/草药，但这些药物须在随机分组前停止使用；
4)至少有一个符合RECISTv1.1的可测量病灶(附件2，根据RECISTv1.1要求该可测量病灶螺旋CT扫描长径≥10mm或肿大淋巴结短径≥15mm)；经过局部治疗的病灶，如明确证据证实，较治疗结束后有显著进展，可选为靶病灶；
5)Child-Pugh肝功能分级：A级或B7；
6)ECOGPS评分：0～1分.
5.3研究方案
抗CTLA-4抗体，C1D1给予280mg，自C5D1起，70mg，Q6W，静脉输注；
抗PD-L1抗体，1200mg,静脉输注，Q3W；
抗VEGF抗体，15mg/kg，静脉输注，Q3W，每3周为一个治疗周期。
5.4结果评价
有效性:1)BIRC基于实体瘤疗效评价标准1.1版(RECIST v1.1)评估的PFS、TTP、DCR、DoR及TTR；2)研究者基于RECIST v1.1评估的PFS、TTP、ORR、DCR、DoR及TTR；3)BIRC基于改良的RECIST(mRECIST)评估的PFS、TTP、ORR、DCR、DoR及TTR。
安全性：1)依据美国国家癌症研究所-不良事件通用术语标准第5.0版(NCI-CTCAE v5.0)判断不良事件(AE)、严重不良事件(SAE)的发生率、严重程度与研究药物的相关性；2)生命体征、心电图和实验室检查异常等。

Claims (20)

  1. 抗PD-L1抗体和抗CTLA-4抗体联合在制备治疗肿瘤的药物中的用途；其中：
    所述抗PD-L1抗体包含重链可变区(VH1)和轻链可变区(VL1)，所述VH1包含分别如SEQ ID NO:1，SEQ ID NO:2和SEQ ID NO:3所示的HCDR1，HCDR2和HCDR3，和所述VL1包含分别如SEQ ID NO:4，SEQ ID NO:5和SEQ ID NO:6所示的LCDR1，LCDR2和LCDR3；和/或，
    所述抗CTLA-4抗体包含重链可变区(VH2)和轻链可变区(VL2)，所述VH2包含分别如SEQ ID NO:11，SEQ ID NO:12和SEQ ID NO:13所示的HCDR1，HCDR2和HCDR3，所述VL2包含分别如SEQ ID NO:14，SEQ ID NO:15和SEQ ID NO:16所示的LCDR1，LCDR2和LCDR3。
  2. 根据权利要求1所述的用途，其中，所述抗PD-L1抗体包含重链可变区(VH1)和轻链可变区(VL1)，所述VH1包含如SEQ ID NO:7所示或与之具有至少80％、90％同一性的氨基酸序列，和，所述VL1包含如SEQ ID NO:8所示或与之具有至少80％、90％同一性的氨基酸序列；
    优选地，所述抗PD-L1抗体包含重链和轻链，所述重链包含SEQ ID NO:9所示或与之具有至少80％、90％同一性的氨基酸序列，所述轻链包含如SEQ ID NO:10所示或与之具有至少80％、90％同一性的氨基酸序列。
  3. 根据权利要求1或2所述的用途，其中，所述抗CTLA-4抗体包含重链可变区(VH2)和轻链可变区(VL2)，所述VH2包含如SEQ ID NO:17所示或与之具有至少90％同一性的氨基酸序列，所述VL2包含如SEQ ID NO:18所示或与之具有至少90％同一性的氨基酸序列；
    更优选地，所述抗CTLA-4抗体包含重链和轻链，所述重链包含如SEQ ID NO:19所示或与之具有至少80％、90％同一性的氨基酸序列，所述轻链包含如SEQ ID NO:20所示或与之具有至少80％、90％同一性的氨基酸序列。
  4. 根据权利要求1-3任一项所述的用途，其中，所述抗PD-L1抗体的给药剂量为50-5000mg，优选为约100mg，约500mg，约800mg，约1000mg，约1200mg，约1500mg，约1800mg，约2000mg，约2200mg，约2500mg，约3000mg；或，所述抗PD-L1抗体的给药剂量为1mg/kg-500mg/kg，优选为约5mg/kg，约8mg/kg，约10mg/kg，约12mg/kg，约15mg/kg，约18mg/kg，约19mg/kg，约20mg/kg，约21mg/kg，约22mg/kg，约23mg/kg，约25mg/kg，约30mg/kg，约40mg/kg，或约50mg/kg；和/或，
    所述抗PD-L1抗体的给药频率为每2周1次，每3周1次，每4周1次，或每6周1次，优选为每3周1次或每4周1次。
  5. 根据权利要求1-4任一项所述的用途，其中，所述抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次；或，所述给药剂量为约15mg/kg或约20mg/kg，给药频率为每3周1次。
  6. 根据权利要求1-5任一项所述的用途，其中，所述抗CTLA-4抗体的给药方案选自：
    (1)给药剂量为0.1-50mg/kg，给药一次或多次；优选为0.5-10mg/kg，给药一次或多次；
    或，
    (2)给药剂量为5-1000mg，给药一次或多次；优选为100-400mg，给药一次或多次。
  7. 根据权利要求1-6任一项所述的用途，其中，所述抗CTLA-4抗体的给药方案选自：
    (1)给药剂量为3.5-10mg/kg，给药一次或两次；优选为约3.5mg/kg、约4mg/kg、约4.5mg/kg、约5mg/kg、约5.5mg/kg或约6mg/kg；
    (2)给药剂量为220-360mg给药一次或两次；优选为约220mg，约240mg，约260mg，约280mg，约300mg，约320mg，约340mg，或约360mg；
    (3)给药剂量为0.5-3.5mg/kg，每3周1次、每6周1次或每9周1次给药；优选为约0.5mg/kg，约1.0mg/kg，约1.5mg/kg，约2mg/kg，约2.5mg/kg，约3.0mg/kg或约3.5mg/kg；
    和/或，
    (4)给药剂量为30-220mg，每3周1次、每6周1次或每9周1次给药；优选为约30mg，约40mg，约50mg，约60mg，约70mg，约80mg，约90mg，约100mg，约120mg，约150mg，约170mg，约190mg，或约200mg。
  8. 根据权利要求1-7任一项所述的用途，其中，所述抗CTLA-4抗体的给药方案包括给药期I和给药期II；
    (a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为3.5-10mg/kg/次，优选为约3.5mg/kg、约4mg/kg、约4.5mg/kg、约5mg/kg、约5.5mg/kg、约6mg/kg或约8mg/kg；
    (a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为0.5-3.5mg/kg，或30-150mg；优选为约0.5mg/kg，约1.0mg/kg，约1.5mg/kg，约2mg/kg，约2.5mg/kg，约3.0mg/kg或约3.5mg/kg；或者，约30mg，约50mg，约60mg，约65mg，约70mg，约75mg，约80mg，约90mg，约100mg，约120mg，或约150mg；
    或者，
    (a1)在给药期I，所述抗CTLA-4抗体给药一次或两次，给药剂量为220-360mg/次，优选为约220mg，约240mg，约260mg，约270mg，约280mg，约290mg，约300mg，约320mg，约340mg，或约360mg；
    (a2)在给药期II，所述抗CTLA-4抗体按照每6周1次给药，给药剂量为0.5-3.5mg/kg，或30-150mg；优选为约0.5mg/kg，约1.0mg/kg，约1.5mg/kg，约2mg/kg，约2.5mg/kg，约3.0mg/kg或约3.5mg/kg；或者，约30mg，约50mg，约60mg，约65mg，约70mg，约75mg，约80mg，约90mg，约100mg，约120mg，或约150mg。
  9. 根据权利要求1-8任一项所述的用途，其中，所述抗CTLA-4抗体的给药方案选自：
    (1)给药剂量为约4.0mg/kg或约280mg，给药一次或两次；
    (2)给药剂量为约1.0mg/kg，每3周1次、每6周1次或每9周1次给药；
    (3)在给药期I给药一次或两次，给药剂量为约4.0mg/kg/次；然后，在给药期II每6周1次给药，给药剂量为约1.0mg/kg；或者，
    (4)在给药期I给药一次或两次，给药剂量为约280mg/次；然后，在给药期II每6周1次给药，给药剂量为约70mg。
  10. 根据权利要求1-8任一项所述的用途，其进一步联合化疗剂、具有抗肿瘤活性的抗体、抗体药物偶联物、和/或抗血管生成剂；
    优选地，所述抗血管生成剂为抗VEGF抗体；
    优选地，所述化疗剂是基于肿瘤组织分型的含铂化疗。
  11. 根据权利要求1-10任一项所述的用途，其中，抗PD-L1抗体和抗CTLA-4抗体联合抗VEGF抗体用于治疗肿瘤；优选地，所述抗VEGF抗体包含重链可变区(VH)和轻链可变区(VL)，所述VH包含分别如SEQ ID NO:21，SEQ ID NO:22和SEQ ID NO:23所示的HCDR1，HCDR2和HCDR3，所述VL包含分别如SEQ ID NO:24，SEQ ID NO:25和SEQ ID NO:26所示的LCDR1，LCDR2和LCDR3；
    优选地，所述VH包含如SEQ ID NO:27所示或与之具有至少90％同一性的氨基酸序列，所述VL包含如SEQ ID NO:28所示或与之具有至少90％同一性的氨基酸序列；
    更优选地，所述抗VEGF抗体包含重链和轻链，所述重链包含如SEQ ID NO:29所示或与之具有至少90％同一性的氨基酸序列，所述轻链包含如SEQ ID NO:30所示或与之具有至少90％同一性的氨基酸序列。
  12. 根据权利要求11所述的用途，其中，所述抗VEGF抗体的给药剂量为约0.5mg/kg至约500mg/kg，优选为约1mg/kg至约50mg/kg；和/或，
    所述抗VEGF抗体的给药频率选自约2周1次、约3周1次、约4周1次、约6周1次、约8周1次或约10周1次，优选为约3周1次；
    优选地，所述抗VEGF抗体的给药剂量为约15mg/kg，给药频率为约3周1此。
  13. 根据权利要求1-12任一项所述的用途，其中，所述抗PD-L1抗体和抗CTLA-4抗体联合化疗剂用于治疗肿瘤；其中，所述化疗剂是基于肿瘤组织分型的含铂化疗；
    优选地，抗PD-L1抗体和抗CTLA-4抗体联合铂类药物以及嘧啶类抗肿瘤药物、紫杉醇、白蛋白紫杉醇、培美曲塞中的一种或多种用于治疗肿瘤；
    优选地，所述嘧啶类抗肿瘤药物为吉西他滨；所述抗PD-L1抗体和抗CTLA-4抗体联合吉西他滨和顺铂用于治疗肿瘤；
    优选地，所述铂类药物选自顺铂、卡铂、奈达铂、奥沙利铂和/或洛铂。
  14. 根据权利要求1-13任一项所述的用途，其中，所述肿瘤为实体瘤，优选为恶性实体瘤；优选为肝癌、肺癌(例如，小细胞肺癌或非小细胞肺癌)、或胆道癌。
  15. 根据权利要求14所述的用途，其中，所述肿瘤为肝癌；所述肝癌优选为不可切除的局部晚期或转移性肝癌，和/或，BCLC分期为B期或C期肝癌。
  16. 根据权利要求14所述的用途，其中，所述肿瘤为非小细胞肺癌，优选为鳞状或非鳞状NSCLC；优选为驱动基因阳性非小细胞肺癌；优选为PD-L1 TPS＜50％的非小细胞肺癌；
    优选地，所述驱动基因阳性的非小细胞肺癌为STK11、KEAP1、KRAS突变或共突变的非小细胞肺癌。
  17. 根据权利要求14所述的用途，其中，所述肿瘤为胆道癌；优选为胆囊癌、肝内胆管癌、肝外胆管癌；更优选为局部晚期、复发和/或转移性的胆囊癌、肝内胆管癌、肝外胆管癌。
  18. 治疗肿瘤的方法，其包括向有需要的受试者施用治疗有效量的抗PD-L1抗体和抗CTLA-4抗体；其中，所述抗CTLA-4抗体的给药方案如权利要求6-9任一项所述；优选地，所述抗PD-L1抗体的给药方案如权利要求4或5所述；
    优选地，所述抗PD-L1抗体如权利要求1或2所述，所述抗CTLA-4抗体如权利要求1或3所述，所述肿瘤如权利要求14-17任一项所述。
  19. 治疗肿瘤的方法，其包括向有需要的受试者施用治疗有效量的抗PD-L1抗体和抗CTLA-4抗体；其中，(a)所述抗CTLA-4抗体的抗给方案选自：
    (1)所述抗CTLA-4抗体的给药剂量为约4.0mg/kg，给药一次或两次；
    (2)所述抗CTLA-4抗体的给药剂量为约280mg，给药一次或两次；
    (3)在给药期I给药一次或两次，给药剂量为约4.0mg/kg/次；然后，在给药期II每6周1次给药，给药剂量为约1.0mg/kg；或，
    (4)在给药期I给药一次或两次，给药剂量为约280mg/次；然后，在给药期II每6周1次给药，给药剂量为约70mg；
    和，(b)所述抗PD-L1抗体的给药剂量为约15mg/kg或约20mg/kg，给药频率为每3周1次；或，所述抗PD-L1抗体的给药剂量为约1200mg或约1800mg，给药频率为每3周1次；
    优选地，所述抗PD-L1抗体如权利要求1或2所述，所述抗CTLA-4抗体如权利要求1或3所述，所述肿瘤如权利要求14-17任一项所述。
  20. 根据权利要求18或19所述的方法，其中，所述方法还包括施用化疗剂、具有抗肿瘤活性的抗体和/或抗体药物偶联物、和/或抗血管生成剂；所述抗血管生成剂优选如权利要求11或12所述，所述化疗剂优选如权利要求13所述；
    优选地，所述方法包括施用：
    (1)抗PD-L1抗体、抗CTLA-4抗体和抗VEGF抗体；
    (2)抗PD-L1抗体、抗CTLA-4抗体和化疗剂；
    优选地，所述方法包括施用：
    (1)抗PD-L1抗体、抗CTLA-4抗体和抗VEGF抗体；
    (2)抗PD-L1抗体、抗CTLA-4抗体和基于肿瘤组织分型的含铂化疗；或，
    (3)抗PD-L1抗体、抗CTLA-4抗体、吉西他滨和顺铂。
PCT/CN2025/100955 2024-06-13 2025-06-13 抗pd-l1抗体和抗ctla-4抗体联合治疗肿瘤 Pending WO2025256641A1 (zh)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017084495A1 (zh) * 2015-11-17 2017-05-26 江苏恒瑞医药股份有限公司 Pd-l1抗体、其抗原结合片段及其医药用途
CN106913869A (zh) * 2017-03-17 2017-07-04 信达生物制药(苏州)有限公司 一种抗ctla‑4单克隆抗体制剂及其应用
WO2018210230A1 (zh) * 2017-05-16 2018-11-22 江苏恒瑞医药股份有限公司 一种pd-l1抗体药物组合物及其用途
CN110505882A (zh) * 2017-03-31 2019-11-26 默沙东公司 用pd-1的拮抗剂和抗ctla4抗体的组合治疗癌症的组合物和方法
CN112638403A (zh) * 2018-07-03 2021-04-09 康泰伦特药物解决方案有限责任公司 包括饰胶蛋白聚糖的多功能蛋白质分子及其用途
CN114729054A (zh) * 2020-05-12 2022-07-08 阿斯利康(瑞典)有限公司 使用免疫检查点抑制剂抗体治疗癌症的方法和组合

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017084495A1 (zh) * 2015-11-17 2017-05-26 江苏恒瑞医药股份有限公司 Pd-l1抗体、其抗原结合片段及其医药用途
CN106913869A (zh) * 2017-03-17 2017-07-04 信达生物制药(苏州)有限公司 一种抗ctla‑4单克隆抗体制剂及其应用
CN110505882A (zh) * 2017-03-31 2019-11-26 默沙东公司 用pd-1的拮抗剂和抗ctla4抗体的组合治疗癌症的组合物和方法
WO2018210230A1 (zh) * 2017-05-16 2018-11-22 江苏恒瑞医药股份有限公司 一种pd-l1抗体药物组合物及其用途
CN112638403A (zh) * 2018-07-03 2021-04-09 康泰伦特药物解决方案有限责任公司 包括饰胶蛋白聚糖的多功能蛋白质分子及其用途
CN114729054A (zh) * 2020-05-12 2022-07-08 阿斯利康(瑞典)有限公司 使用免疫检查点抑制剂抗体治疗癌症的方法和组合

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